Method (versions) and preparation for modification of eating behaviour

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and can be used for modification of eating behaviour in a subject. For this purpose peripheral introduction of PYY in an amount, efficient for achieving physiological levels of PYY_3-36 in blood, plasma and serum, determined after food intake, is performed; or performed is peripheral introduction of PYY agonist in an amount, efficient for imitation of physiological levels of PYY_3-36 in blood, plasma or serum, determined after food intake with modification of eating behaviour, by reducing intake of calories, food consumption or appetite reduction or increase of energy consumption in the subject. Also claimed is application of PYY or its agonist as an active ingredient in production of medication.

EFFECT: group of inventions provides weight reduction in the subject due to reduction of intake of calories, appetite reduction or increase of energy consumption in the subject.

50 cl, 9 dwg, 6 ex

The technical field to which the invention relates.

This invention relates to a method of modifying feeding behavior and the use of agents for appetite control, nutrition, food intake, energy expenditure and calorie intake, especially in the case of obesity.

Relevant studies were carried out with the support of the government of the United States in accordance with grants from the National Institute of health RR00163, DK51730 and DK55819. The United States government has certain rights to this invention.

The level of technology

According to the State inspection services health and nutrition (National Health and Nutrition Examination Survey (NHANES III, 1988-1994), from one-third to one-half of men and women in the U.S. are overweight. In the U.S. sixty percent of men and fifty-one percent of women aged 20 years and older are either overweight or obese. In addition, in the U.S. a large percentage of children are overweight or obese.

The cause of obesity is complex and multifactorial. There is a growing amount of data that suggest that obesity is not just a problem of self-control, but a complex violation, including the regulation of appetite and energy metabolism. In addition, obesity is associated with many conditions associated povyshennoi morbidity and mortality. Although the etiology of obesity has not been settled, I believe that it involves genetic, metabolic, biochemical, cultural and psychological factors. Generally, obesity is described as a condition in which excess body fat is a risk factor for the health of the subject.

There is strong evidence that obesity is associated with increased morbidity and mortality. The risk of developing diseases, such as the risk of developing cardiovascular disease and the risk of developing type 2 diabetes, independently increases with increasing body mass index (VM). In fact, this risk is quantified as an increase of five percent risk of developing heart disease in women and increased by seven percent risk of developing heart disease in men for each item VM exceeding 24,9 (see article Kenchaiah et al., N. Engl. J. Med. 347:305, (2002); Massie, N. Engl. J. Med. 347:358, (2002)). In addition, there is strong evidence that weight loss in subjects with obesity reduces the risk factors for serious diseases. Even a small weight loss, such as 10% of baseline body weight in adult subjects with overweight and obesity, was associated with decreased risk factors, e.g. hypertension, hyperlipidemia and hyperglycemia.

Although dieta physical exercises are an easy way to reduce weight gain, subjects with overweight and obesity, often are not able to control these factors for the effective loss of body weight. There is a possibility of pharmacotherapy. The management under the control over products and medicines approved several drugs for weight loss, which can be used as part of a comprehensive program of weight loss. However, many of these drugs have serious adverse side effects. The ineffectiveness of the use of less invasive methods, and if there is a high risk for the patient of developing obesity-related diseases or death of an option for carefully selected patients with clinically severe obesity is a surgical intervention aimed at weight loss. However, these methods of treatment are high risk and are suitable for use only on a limited number of patients. Not only the subjects with obesity wish to reduce body weight. People with body mass, which is within the recommended boundaries, for example in the upper pane of the recommended interval may be willing to reduce the weight of your body with the purpose of bringing it closer to the ideal body weight. Thus, there remains a need for agents that can be used to influence namasu body in subjects with overweight or obesity.

Disclosure of inventions

In this context, presents the information that the peripheral introduction to the subject of the PYY or agonist results in reduced absorption of food, calorie intake and appetite, and changes of energy metabolism. The subject can be any subject, including, but not limited to, humans. In some embodiments, the subject who wants to lose weight, is obese, overweight, or suffering from disorders associated with body weight. Preferred may be the introduction to the subject PYY_3-36.

In one of the embodiments described by way of reducing calorie intake in a subject. The method includes the peripheral introduction to a subject a therapeutically effective amount of PYY or the agonist to reduce, thus, consumption subject calories.

In another embodiment, described by way of loss of appetite in the subject. The method includes the peripheral introduction therapeutically effective amount of PYY or agonist to a subject to reduce thus the appetite of the subject.

In the following embodiment describes a method of reducing the absorption of food in the subject. The method includes the peripheral introduction therapeutically effective amount of PYY or agonist to a subject for snizeni is thus absorption of food in the subject.

In another embodiment, in this context, the described method of increasing energy expenditure in a subject. The method includes the peripheral introduction therapeutically effective amount of PYY or agonist to a subject to increase thus the energy expenditure of the subject.

There is also described a method of reducing calorie intake, food intake or appetite of the subject person. The method includes peripheral injection to a subject a therapeutically effective amount of PYY or the agonist in a pharmaceutically acceptable carrier in pulse dose to reduce thus calorie intake, food intake, or appetite for the subject.

In this context, presents the information that the peripheral introduction to the subject of PYY antagonist results in increased food intake, calorie intake and appetite, as well as the change in energy metabolism. The subject can be any subject, including, but not limited to, humans. In some embodiments, the implementation of the subject wants to increase body weight or suffering from anorexia or cachexia.

The above and other features and advantages will be more apparent from the subsequent detailed description of some embodiments, which is preceded by a reference to the accompanying figures.

Brief description of drawings

The Figure 1 presents a set of graphs and digital images showing the obtaining of transgenic mice expressing EGFP (protein, green fluorescence) in the O.G. ROMs (proopiomelanocortin) neurons in the ARC (arcuate nucleus). Figure 1 is a schematic diagram of the structure of the transgene POMC-EGFP. Figure 1A presents a digital image showing the identification of one O.G. ROMs neuron (arrow) using EGFP fluorescence (top) and IR-DIC microscopy (bottom) in the living slice ARC before registering electrophysiological data. Figure 1C presents a set of digital images showing colocalization (light, right) EGFP immunoreactivity (left) and β-endorphin (in the middle) in neurons O.G. ROMs in the arcuate nucleus. The columns showing the image scale: b and C, 50 μm. Figure 1d presents a set of diagrams showing the distribution of EGFP-positive soma of neurons in the core of the ARC. O = 5 cells, • = 10 cells.

The Figure 2 presents the recording of the recording instrument and graphs demonstrating that activation of the MOP-Rs leads to hyperpolarization of neurons O.G. ROMs labeled EGFP, by opening the G-protein-coupled potassium channels of internal regulation. Figure 2A presents the recording of the recording instrument, which shows that the met-enkephalin leads to hyperpolarization of neurons RUM and inhibits all action potentials. The horizontal bar indicates the time at which 30 mm Met-Enk put on a slice by immersion. Figure 2b presents a graph showing the shift of the current met-enkefalina and potential reversion under the influence of the extracellular concentrations of K⁺. Figure 2C presents a graph showing that the met-enkephalin activates MOP-R neurons O.G. ROMs. See the current Met-Enk (30 μm), and within 1 minute act MOP-R-specific OLD antagonist (1 μm). Further the influence of the OLD Met-Enk does not cause a shock. The figure presents data for the three experiments.

The Figure 3 presents the records of the registering devices and graphs demonstrating that leptin depolarizes neurons O.G. ROMs, acting through non-specific cation channel, and reduces GABAergic signal cells O.G. ROMs. Figure 3A presents the records of the registering devices, demonstrating that leptin depolarizes neurons O.G. ROMs and increases the frequency of action potentials in the range from 1 to 10 minutes after injection. The figure is a representative example of the recordings made by 77 neurons O.G. ROMs. Figure 3b presents a graph showing that leptin causes dependent on the concentration depolarization of cells O.G. ROMs. The depolarization caused by leptin, determined as 0.1, 1, 10, 50, and 100 nm (EC=5,9 nm) (8, 7, 9, 3, 45) cells, respectively. Figure 3C presents a graph p is practice showing, that leptin depolarizes cells O.G. ROMs by activated nonspecific cationic current. The figure represents the reaction in 10 cells. Figure 3d presents a graph showing that leptin reduces the frequency of IPSCS in cells O.G. ROMs. On the Figure as an example, there are 5 cells in which leptin (at a concentration of 100 nm) reduced the frequency of IPSCS. In Figure 3E presents the record of the registration devices, demonstrating that leptin has no effect on 5 adjacent afluorescent neurons in the ARC. Figure 3f shows the record of registration of the devices, showing that leptin causes hyperpolarization 5 afluorescent neurons in the ARC.

The Figure 4 presents a set of images, showing that GABAergic inputs in cells O.G. ROMs come from NPY neurons, which coexpression GABA. Figure 4A is a graph showing that NPY increases the frequency miniIPSCS in neurons O.G. ROMs. Figure 4b shows a graph demonstrating that D-Trp⁸-yMSH (7 nm)at a dose, which selectively activates the MC3-R, increases the frequency of GABAergic IPSCS in neurons O.G. ROMs. Figure 4C presents the record of registration of the devices, showing D-Trp⁸-yMSH causing hyperpolarization of neurons O.G. ROMs. Figures 4A, 4b and 4C are representative. Figure 4d presents the set of digital images showing the expression of NPY in the nerve endings, Prime is asih to neurons O.G. ROMs ARC. Nerve endings NPY (black arrows); soma of neurons O.G. ROMs (shown in gray). The column showing the scale has a size of 10 μm. Figure 4E shows a digital image showing the expression of GABA and NPY in the nerve endings of synapses on neurons in the ARC. GABA immunoreactivity (gold particle size of 10 nm, arrows without tail) and NPY immunoreactivity (gold particle size 25 nm, an arrow with a tail) are in separate populations of vesicles, colocalization in synaptic buds that provide direct contact with the soma of neurons O.G. ROMs (DAB when the contrast uranylacetate and lead citrate, diffuse black staining of the cytoplasm). The column that indicates the scale, 1 μm. Figure 4f is a diagram of the model NPY/GABA and neurons O.G. ROMs in the ARC.

The Figure 5 presents a set of graphs relating to food reactions of rats to PYY3-36. Figure 5A is a graph in the form of columns of power in the dark phase, which reduces the data by the absorption of food after intraperitoneal injection of PYY3-36. Rats with free access to food by injection was administered PYY_3-36these doses (μg/100 g) or saline immediately before turning off the light and measured the cumulative absorption of food in 4 hours. The results are presented as mean ± s.e.m. (standard the percentage error) (n=8/group), *=p<0,05, **=p<0,01, ***=<0,001 relatively saline. Figure 5b shows a graph in the form of columns, reflecting the absorption of food after intraperitoneal injection of PYY_3-36. Subjected to fasting rats by injection was administered PYY_3-36these doses (μg/100 g) or saline and measured cumulative absorption of food in 4 hours. The results are presented as mean ± s.e.m. (n=8/group), *=p<0,05, **=p<0,01, ***=<0,001 relatively saline. Figure 5C shows a graph in the form of columns, reflecting the cumulative absorption of food after intraperitoneal injection of saline or PYY_3-36. Subjected to fasting rats intravenously injected with either saline (black bars)or PYY_3-36at a dose of 5 µg/100 g (white bars) and measured cumulative absorption of food in the specified time points. The results are expressed as mean ± s.e.m. (n=12/group), **=p<0,01 relative to saline. Figure 5d shows a line graph of the increase of body weight during chronic treatment PYY_3-36. Rats by intraperitoneal injection twice a day for 7 days was administered PYY_3-36at a dose of 5 µg/100 g (white squares) or saline (black inverted triangles). The increase in body mass was calculated daily the VNO. The results are expressed as mean ± s.e.m. (n=12/group), **=p<0,01 relative to saline.

The Figure 6 presents a set of digital images of the expression of c-fos in mice Pomc-EGFP. In Figures 6A and 6b presents digital images of representative sections (parietal region - 1.4 mm²reflecting the expression of c-fos in the arcuate nucleus of the mouse Pomc-EGFP in response to intraperitoneal injection of physiological solution (see Figure 6A) or PYY_3-36(5 μg/100 g) (see Figure 6b). The line showing the image scale to 100 μm. 3V - third ventricle; ARC, arcuate nucleus. In Figures 6C and 6d presents digital images of representative sections showing the neuronal POMC-EGFP (see Figure 6C) and immunoreactivity (c-fos (see Figure 6d) or colocalization (light arrows), either separately from each other (one darker arrow). The line showing the zoom, 25 mm.

The Figure 7 presents the set of graphs in the form of columns, reflecting the rat PYY_3-36in the arcuate nucleus and the effects on food intraperitoneal administration of PYY_3-36mice Y2r-null. Figure 7a shows a graph in the form of columns of the absorption of food after injecting PYY_3-36in the arcuate nucleus. Subjected to fasting rats intravenously injected with saline or PYY_3-36in the arcuate who draw these doses. 2 hours after injection was measured by the absorption of food, **=p<0.01 relative to saline. In Figures 7b and 7C shows the graphs in the form of columns, reflecting food response to PYY_3-36in mice Y2r-null after intraperitoneal administration: the offspring of wild-type mice (see Figure 7b) and mice Y2r-null (see Figure 7C), subjected to starvation for 24 hours, were injected with PYY_3-36these doses (μg/100 g) or saline and measured cumulative absorption of food within 4 hours. The results are presented as mean ± s.e.m. (n=5/group), *=p<0,05, **=p<0,01 relative to saline.

The Figure 8 presents a set of images related to electrophysiological and neuropeptide response to PYY_3-36and Y2A. Figure 8A presents the account of the registering device, showing the effect of PYY_3-36(concentration 10 nm) on the frequency of action potentials in neurons O.G. ROMs (entries for whole cell configuration; n=22) * p<0,05. PYY_3-36enter during D for 3 minutes; line base level - 3 - 0 minutes; PYY_3-362-5 minutes and laundering 8-11 minutes. The insert shows a representative recording of the membrane potential and the pulse frequency of the action potential. Figure 8b presents a bar graph showing the effect of PYY_3-36(at a concentration of 10 nm) at a repetition rate of impul the owls of action potential in the records of the potential of the patch-clamp with a free attaching cells (n=8). Data characterizing individual cells, normalized to the number of pulses over a period of 200 s to add PYY_3-36. Figure 8C shows the recording of the recording instrument and a graph of the effect of PYY_3-36(at a concentration of 50 nm) on spontaneous IPSCS in neurons O.G. ROMs (n=13). The inset shows a representative recording IPSCS before and after adding PYY_3-36(concentration 50 nm), respectively. The results, shown in Figures 8A-8C expressed as mean ± s.e.m. In Figures 8d and 8E show charts in the form of columns, showing the release of NPY (see Figure 8d) and α-MSH (see Figure 8E) from hypothalamic explants in response to Y2A. Slices of hypothalamus incubated with artificial CSF (aCSF) with addition or without addition of 50 nm Y2A within 45 minutes. The results are expressed as mean ± s.e.m. (n=40), **=p<0,01, ***=p<0,001 relatively saline solution.

The Figure 9 presents a set of graphs showing the effect of PYY infusion_3-36on appetite and absorption of food in humans. Figure 9a shows the graph of the consumption of calories from freely chosen snacks 2 hours after infusion of saline or PYY_3-36. Thin lines show individual changes in consumption of calories each subject with the introduction of saline solution and PYY_3-36. The thick line represents the average change, proishodiashie the two options infusion (n=12). Figure 9b is a graph of a 24-hour calorie intake after infusion of saline or PYY_3-36. Total calorie intake is shown for a 24-hour period after infusion of either saline or PYY_3-36based on the assessment using the log supply. Data are shown as mean ± s.e.m. (n=12), [***]=p<0,0001 relatively saline. Figure 9c shows a graph of the accounting appetite (relative scale). Analog visual system into account (see Raben et al., Br. J. Nutr., 73:517-30, (1995)) show the feeling of hunger during and after infusion. The results are presented as deviation from the baseline, and they are average values + s.e.m. all 12 subjects.

The list of sequences

Nucleic acid sequences and amino acids listed in the attached list of sequences shown using standard letter abbreviations for nucleotide bases, and a letter code for amino acids as defined in 37C.F.R. 1.822. Shown is only one strand of each nucleic acid sequence, but the inclusion of complementary thread means in the form of any link to the thread.

The implementation of the invention

I. Abbreviations

α-MSH: α-melanocortin-stimulating hormone

ARC: bhoop is the heat kernel

EPSP: excitatory postsynaptic potential

GABA: γ-aminobutyric acid

GFP, EGFP: protein green fluorescence

IPSCS: brake postsynaptic current

TPN: kilobase, (thousand base pairs)

kg: kilogram

MOP-R: mu-opioid receptor

mV: millivolts

NPY: neuropeptide Y

pmol: picomol

O.G. ROMs: proopiomelanocortin

RIA: radioimmunoassay

RPA: analysis of the RNase protection

s.e.m: standard error

T: tyrosine hydroxylase

mkm: micropoly

In: volt

Y2A: N-acetyl(Leu²⁸,Leu³¹)NPY(24-36)

II. Terms

Unless otherwise noted, technical terms are used in accordance with in this area of their interpretation. Definitions of terms common in molecular biology, can be found in the monograph by Benjamin Lewin, Genes V (Genes V, published by Oxford University Press, (1994) (ISBN 0-19-[854287-9)]; in the monograph edited by Kendrew et al. Encyclopedia of molecular biology (The Encyclopedia of Molecular Biology), published by Blackwell Science Ltd., (1994) (ISBN 0-632-02182-9) and the monograph edited by Robert A. Meyers, a Complete desktop reference for molecular biology and biotechnology (Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., (1995) (ISBN 1-56081-569-8).

To facilitate examination of the various embodiments of this discovery presents the following explanations of specific terms.

Potential action:rapidly spreading an electrical signal, that is axona neuron and the surface membrane of many muscle and glandular cells. In axona they are short, are held constant speed and maintain a constant amplitude. As all the electrical signals of the Central nervous system, the action potential is a change in membrane potential caused by the flow of ions through membrane channels. In one embodiment, the implementation of the action potential is a regenerative wave permeability of sodium.

Animal: living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and mammals other than humans. Similarly, the term "subject" includes both human and objects of veterinary medicine.

Anorexia: Lack or loss of appetite caused by food. In one embodiment, the implementation of anorexia is the result of "anorexia nervosa". This food violation mainly affects women, usually at the beginning of puberty. It is characterized by refusal to maintain a normal minimal body weight, intense fear of weight gain or obesity, and anxiety about the appearance of the body, resulting in the feeling that some parts of the body get fat or thick steel Yes the e in cases of severe depletion, unjustified confidence in their own assessment of the weight or shape of the body and causes amenorrhea. Accompanying symptoms often include denial of the disease and immunity to psychotherapy, depression symptoms, significantly reduced libido and obsession (obsession) or specific behavior with respect to food, such as the storage of food. Violations are divided into two subtypes - restricting type, in which the weight loss is achieved primarily through diet or exercise, and the type associated with overeating/the cleansing of the body, in which the behavior of overeating or cleansing also occur regularly.

Antagonist: a Substance, the trend of activity of which is to cancel the actions of another, as in the case of an agent which binds to a cell receptor without causing biological reactions by blocking the binding of substances that could cause such reactions.

Appetite: a Natural desire or desire for food. In one of the embodiments, the appetite is measured through a survey to assess the desire for food. Increased appetite, usually leads to increased eating behavior.

Drugs to suppress appetite: Connection, reducing the desire for food. Commercially available drugs to suppress appetite include without limitation amfepramone (diethylpropion), intermin, mazindol and phenylpropanolamine fenfluramin, dexfenfluramin and fluoxetine.

Binding: Specific interaction between two molecules such that the two molecules interact. Binding may be specific and selective, with one molecule has an advantage in binding compared to the other molecule. In one embodiment, the implementation of specific binding identifies the dissociation constant (K_d).

The body mass index (VM): Mathematical formula for measuring the mass of the body, sometimes also called the Quetelet index. BMI is calculated by dividing body weight (in kg) on the growth of²(m²). According to the modern standards for men and women for "normal" take VM 20-24 .9 kg/m². In one of the embodiments VM greater than 25 kg/m²can be used to identify obesity in the subject. I degree obesity corresponds VM 25-29,9 kg/m². Obesity II corresponds VM 30-40 kg/m²and obesity III corresponds VM more than 40 kg/m²(see article Jequier, Am. J. Clin. Nutr., 45: 1035-47, (1987)). Ideal body weight will vary among species and individuals, depending on the size, shape, bone structure, and sex.

c-fos: Cellular homolog of the viral oncogene v-fos found in FBJ (Finkel-Biskis-Jinkins) and viruses of murine osteosarcoma the FBR (MSV). Human fos gene mapped on chromosome 14q21-q31. Human fos identified as TIS-28. Consider that c-fos plays an important role in signal transduction, proliferation and differentiation of cells. He is a nuclear protein, which in combination with other transcription factors (e.g., jun) acts as a TRANS-activating regulator of gene expression. C-fos is an immediate early gene response, which is believed to play a key role in the early response of cells to growth factors. C-fos is also involved in the control of cell growth and differentiation of embryonic hematopoietic cells and nerve cells. Known coding sequences of amino acids and nucleic acids of the human c-fos (for example, see Verma et al., Cold Spring Harb. Symp. Quant. Biol., 51:949, (1986); GenBank registration number K00650 and M 16287, and information on the Internet).

Cachexia: General physical exhaustion and malnutrition, which are often associated with chronic painful process. Cachexia is often noted in patients with cancer, AIDS or other diseases. Cachexia include without limitation 1) cancer cachexia observed in cases of malignant tumors; 2) cardiac cachexia - depletion due to heart disease, which is usually due to a combination of increased consumption of calories is reduced consumption or use of calories; 3) fluorous cachexia, celebrated during fluorosis; 4) pituitary cachexia; 5) the cachexia associated with insufficiency of the pituitary gland is a complex of symptoms occurring from total deprivation pituitary function, including tuberculosis, loss of sexual function, atrophy of the glands associated with the pituitary gland, bradycardia, hypothermia, lethargy, and coma; 6) malarial cachexia - a group of physical signs of a chronic nature, which are caused by previous attacks of severe malaria; 7) mercurialism observed in chronic mercury poisoning; 8) pituitary cachexia disease Simmonds); 9) lead cachexia observed in chronic lead poisoning; 10) suprarenal cachexia associated with Addison disease and 11) uremic cachexia associated with other systemic symptoms of chronic renal failure.

Calorie or calorie intake: calories (energy)consumed by an individual.

Calorie: a Unit of food. Standard calorie is defined as 4,184 absolute joules or the amount of energy needed to raise the temperature of one gram of water from 15 to 16°C (or 1 / 100th of the amount of energy required to raise the temperature of one gram of water at 1 atmosphere pressure from 0°C to 100°C. Food calorie is actually 1000 standard calories (1 of food is Aloria = 1 kcal).

Conservative variation: Replacement of one amino acid residue other, biologically close balance. Examples of conservative variations include the substitution of one hydrophobic residue such as isoleucine, valine, leucine, or methionine, for another, or substitution of arginine, lysine, or by substitution of one polar residue for others, such as the replacement of arginine, lysine, glutamic acid, aspartic acid or glutamine by asparagine, etc. the Term "conservative variation" also includes the use of substituted amino acids instead of the unsubstituted original amino acid provided that antibodies generated to replaced the polypeptide of immunoreactive also with the unsubstituted polypeptide.

Non-limiting examples of conservative substitutions of amino acids include the following replacement:

Depolarization: the Increase of the membrane potential of the cell. Some incentives reduce the charge in the plasma membrane. They can be represented by electrical stimuli (which open capacity-adjustable channels), mechanical stimuli (which can activate mechanically adjustable channels) or certain neurotransmitters (which opens ligand-regulated channels). In each case, the light diffusion of sodium into the cells increases the resting potential at the point on the cell, which creates wosb is proving postsynaptic potential (EPSP). Depolarization can also be created by reducing the frequency of brake postsynaptic currents (IPSCs), which with the help of inhibitory neurotransmitters contribute to the influx of chloride ions into the cell, creating IPSC. With increasing potential to the threshold voltage (approximately 50 mV in neurons mammals) in the cell is the generation of the action potential.

Diabetes: the Inability of cells to be transported through the membrane endogenous glucose as a result of endogenous deficiency of insulin and/or defect in insulin sensitivity. Diabetes is a chronic syndrome metabolic disorders of carbohydrates, proteins or fats due to insufficient secretion of insulin or resistance to insulin target tissue. There are two main forms of diabetes: insulin-dependent diabetes mellitus (IDDM, type I) and leisureservices diabetes mellitus (NIDDM, type II), which differ in etiology, pathology, genetics, age of onset and treatment.

Both major forms of diabetes are characterized by an inability to deliver insulin in a quantity and at the exact time required for the control of glucose homeostasis. Diabetes type I or insulin-dependent diabetes mellitus (IDDM) is caused by the destruction of β-cells, which results in insufficient levels of endogenous insulin. Diabetes type II or Naina savisky diabetes is caused by the defect sensitivity of the body to insulin, and the relative lack of production of insulin.

Binge eating: the Amount of food consumed by a person. The absorption of food can be measured by volume or mass. In one of the embodiments the absorption of food is a food consumed by the person. In another embodiment, the absorption of food presents a number of proteins, fats, carbohydrates, cholesterol, vitamins, minerals, or other dietary components consumed by the person. The term "absorption of proteins" refers to the amount of protein consumed by the person. Similarly, the terms "absorption of fats, absorption of carbohydrates, absorption of cholesterol, absorption of vitamins and mineral absorption" refers to the amount of proteins, fats, carbohydrates, cholesterol, vitamins or minerals consumed by the entity.

The hyperpolarization: a Decrease in the membrane potential of the cell. Inhibiting neurotransmitters inhibit the transmission of nerve impulses by hyperpolarization. This type of hyperpolarization-called brake postsynaptic potential (IPSP for acquiring). Despite the fact that the cell is not charged to the threshold voltage, for hyperpolarizing cells required more strongly stimulating the stimulus to reach the threshold value.

Brake postsynaptic current: the Current that inhibits electrophysiological parameter on sinapticheskoi cells. The potential of the postsynaptic cell can be analyzed to determine the effect on the presynaptic cell. In one embodiment, the implementation of the postsynaptic cell support in the state of fixing the voltage and register postsynaptic currents. If necessary, can be added antagonists of other classes currents. In one specific non-limiting example, for registration GABAergic IPSCs add blockers of excitatory channels or receptors. Then over time to determine the instantaneous frequency.

In one embodiment, the implementation of IPSCs is a measure of the frequency of release of GABA from neurons containing NPY. Because neurons containing NPY secrete GABA on neurons O.G. ROMs, measuring the frequency of IPSCs is a measure of inhibitory signal, which is derived neurons O.G. ROMs, and can be used to evaluate the effect of a PYY agonist.

Membrane potential: the electric potential of the internal part of the cell relative to the environment, such as the solution in which the cell. Competent person skilled in the art can easily determine the membrane potential of cells, for example, using accepted methods using whole cells. Activation of cells associated with a less negative membrane potentials (e.g., shifts from approximately -50 mV to bring is Ino -40 mV). These potential changes increase the probability of occurrence of action potentials and, thus, lead to an increase in the frequency of action potentials.

The repetition frequency of action potentials can be determined using many approaches, such as using the adopted methodology on the basis of whole cells or, for example, using the whole cell configuration with a perforated area or configurations by attaching to cells. Each event is evaluated as not the absolute value of voltage or current, the frequency of the speed deviations characterizing the action potentials, which is determined as a function of time (consequently, this frequency represents the instantaneous frequency, which is represented in "bins"). This temporal component can be associated with a time at which the connection, such as PYY agonist, contribute to the capacity to analyze the effect of the compounds, such as PYY agonist, at a pulse frequency of action potential.

Neuropeptide Y (NY): the Peptide of 36 amino acids, which is a neuropeptide identified in the brain. Believe that NPY is an important regulator of both Central and peripheral nervous system and affects a wide range of physiological parameters, including effects on psychomotor activity, absorption of food, cent the actual endocrine secretion and vasoactivity cardiovascular system. High concentrations of NPY found in the sympathetic nerves, which provides coronary, cerebral and renal vascular network and play a role in vasoconstriction. The NPY binding sites identified in many tissues, including spleen, intestinal membranes, brain, smooth muscle aorta, kidney, testis and placenta. In addition, connecting the centers described in several cell lines of rat and human.

The receptor for neuropeptide Y (NPY) on the structure/activity similar family of peptides in the pancreas. This family includes NPY, which is mainly synthesized in neurons, peptide YY (PYY), which is mainly synthesized in endocrine cells of the intestine, and pancreatic polypeptide (PP), which is mainly synthesized in endocrine cells of the pancreas. These peptide of 36 amino acids have a compact helical structure comprising the amino acid structure called "PP-fold"in the middle of the peptide.

NPY binds to several receptors, including the receptors Y1, Y2, Y3, Y4 (PP), Y5, Y6 and Y7. These receptors recognize affinely associate, pharmacology and sequence (if known). Most, if not all of these receptors are G-protein-coupled receptors. In General, assume that the Y1 receptor is postsynaptic and TNA is Reduit many of the known functions of neuropeptide Y on the periphery. Initially, this receptor is described as having a low affinity to C-terminal fragments of neuropeptide Y, such as the fragment 13-36, but he interacts with neuropeptide Y full length and peptide YY with equal affinity (for example, see PCT publication WO 93/09227).

Pharmacologically Y2 receptor differs from Y1 fact that shows affinity to C-terminal fragments of neuropeptide y Receptor Y2 are most often differentiated by the affinity of neuropeptide Y(13-36), although the fragment 3-36 neuropeptide Y and peptide YY have a high affinity and selectivity (see Dumont et al., Society for Neuroscience Abstracts, 19:726, (1993)). Signaling through both receptors, Y1 and Y2, is associated with inhibition of adenylate cyclase. Also found that the binding of Y receptor-2 reduces intracellular levels of calcium in the synapse by selective inhibition of calcium channel N-type. In addition, the Y receptor-like 2 receptor Y1 various ways associated with secondary messengers (see U.S. Patent No. 6355478). The Y2 receptors are found in many brain regions, including the hippocampus, black substance, the thalamus (visual buttocks), the hypothalamus and the brain stem. The cloned receptor Y2 human, mouse, monkey and rat (for example, see U.S. Patent No. 6420352 and U.S. Patent No. 6355478).

Agonist receptor Y2 represents a peptide, a small mole the Ulu or chemical compound, which are mainly associated with the Y2 receptor and stimulate the transmission of intracellular signals. In one of the embodiments, the agonist of the Y2 receptor binds to the receptor with equal or greater affinity than NPY. In another embodiment, the agonist selectively binds to the Y2 receptor compared with the binding to another receptor.

Competent person skilled in the art can easily determine the value of the dissociation constants (K_d) the specified connection. This value depends on the selectivity of test compounds. For example, compounds with K_dless than 10 nm, typically, is considered a promising candidate drug substance. However, the connection that has a lower affinity, but is selective for a particular receptor, may also be a good candidate drug substance. In one specific non-limiting example, the analysis, such as competitive analysis, are used to determine whether compound interest as an agonist of the receptor Y2. The tests used for evaluation of receptor antagonists of neuropeptide Y, also well known in the art (see U.S. Patent No. 5284839, which is included in this context in the form of links, and an article by Walker et al., Journal of Neurosciences, 8:2438-2446, (1988)).

Normal everyday the diet: the Average absorption of food for individuals of a given species. Normal daily diet can be expressed in terms of calorie intake, protein intake, carbohydrate intake and/or fat intake. For a person of normal daily diet usually provides as follows: approximately 2000, 2400 or approximately 2800 to a significantly larger number of calories. In addition, the normal daily diet of a person, typically includes from about 12 g to about 45 g of protein, from about 120 g to about 610 grams of carbohydrates and about 11 grams to about 90 grams of fat. Low-calorie diet for a man not exceed approximately 85% and preferably about 70% of the normal caloric intake.

Animals needs calories and nutrients vary depending on the type and size of the animal. For example, in cats, the total consumption of calories/pound, and percentage distribution of protein, carbohydrates and fat changes with age and reproductive status of females. However, the General rule for cats is 40 cal./lb/day (18,2 cal./kg/day). From approximately 30% to approximately 40% should be protein, from about 7% to about 10% should be from carbohydrates and from about 50% to about 62.5 percent should come from fat consumption. The competent specialist Dan the Oh region can easily determine the normal daily diet animals of any kind.

Obesity: a Condition in which excess body fat may involve risks to the health of the subject (see Barlow and Dietz, Pediatrics, 102:E29, (1998); National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Obes. Res. 6 (suppl. 2): 51S - 209S, (1998)). Excess body fat is the result of an imbalance of energy intake and energy expenditure. In one of the embodiments, the body mass index (BMI) is used to assess obesity. In one embodiment, the implementation of BMI from 25.0 kg/m²to 29.9 kg/m²is overweight, while a BMI of 30 kg/m²is obesity.

In another embodiment, for the evaluation of obesity using waist circumference. In this embodiment, the waist circumference in men 102 cm or more is considered as obese, whereas in women, obesity is waist circumference 89 cm or more. There are strict evidence that obesity affects the morbidity and mortality of subjects. For example, a subject with obesity have an increased risk of developing heart disease, non-insulin-dependent diabetes (type 2), hypertension, stroke, cancer (such as endometrial cancer, breast cancer, prostate and colon), dyslipidemia, gallbladder disease, seizures sleep apnea, reduced fertility and osteoarthritis, and others (see Lyznicki et al., Am. Fam. Phys., 63:2185, (2001)).</>

Overweight: the Subject, the weight of which exceeds its ideal body weight. The subject with overweight may be obese, but not necessarily obese. In one of the embodiments of the subject with overweight is any entity that wishes to reduce his body weight. In another embodiment, the subject with overweight is subject to VM from 25.0 kg/m²to 29.9 kg/m².

The pancreatic polypeptide: a peptide of 36 amino acids, produced by the pancreas, which has homology with PYY and NPY.

Peripheral introduction: Introduction outside of the Central nervous system. Peripheral introduction does not include the direct introduction into the brain. Peripheral introduction include but are not limited to intravascular, intramuscular, subcutaneous, inhalation, oral, rectal, transdermal or intranasal administration.

Polypeptide: a Polymer in which the monomers are amino acid residues that are linked by an amide bonds. When amino acids are represented by α-amino acids, can be used with either the L-optical isomer or the D-optical isomer, while preferred are L-isomers. The terms "polypeptide" or "protein", as used in this context, are intended for grasping any the second amino acid sequence and include modified sequences, such as glycoproteins. The term "polypeptide" specifically intended to cover natural proteins, and those proteins that received recombinant or synthetic means. The term "polypeptide fragment" refers to a part of the polypeptide, for example, this fragment, which is at least one sequence involved in the binding of the receptor. The term "functional fragments of the polypeptide" refers to all fragments of the polypeptide that retain the activity of the polypeptide. Biologically functional peptides can also include fused protein in which the peptide of interest is fused with another peptide, which does not reduce its desirable activity.

PYY: Peptide polypeptide YY, derived or isolated from any species. Thus, PYY includes a human polypeptide is full length (as shown in SEQ ID NO:1) and species variation of PYY, containing, for example, PYY mouse, hamster, chicken, bovine, rat and dog (SEQ ID NOS:5-12). In one of the embodiments, the PYY agonists do not include NPY. PYY also includes PYY_3-36. "The PYY agonist" is any compound that binds to a receptor that specifically binds a PYY and causes the effect of PYY. In one of the embodiments, the PYY agonist is a compound that affects the absorption of food, sweat is eblana calories or appetite and/or which demonstrates the specific binding analysis using receptor Y or competes for binding with PYY, as in the analysis of competitive binding with labeled PYY. PYY agonists include, but are not limited to, compounds that bind to the Y2 receptor.

Almost cleared: Polypeptide, which contains almost no other proteins, lipids, carbohydrates or other materials with which it is associated in vivo. For example, the polypeptide may be at least 50%, 80% or 90% purified from other proteins, lipids, carbohydrates or other materials with which it is associated in vivo.

Therapeutically effective amount: a Dose sufficient to prevent the development or regression of violation, or is able to alleviate a sign or symptom of the breach, or which can give the desired result. In some embodiments a therapeutically effective amount of PYY or the agonist is an amount sufficient to suppress or stop the increase of body weight, or amount, sufficient to reduce appetite, or amount, sufficient to reduce the consumption of calories or food intake or increase energy expenditure.

If not explained otherwise, all technical and scientific terms used in this context have the same meaning, what usually means an ordinary specialist in the field to which this discovery. Terms in a single h which should include plural, unless the context clearly indicates otherwise. Similarly, the word "or" suggests the inclusion of "and", unless the context clearly indicates otherwise. In addition, it should be understood that all dimensions of the bases or dimensions of amino acids, and all molecular weight or molecular size of the mass, the data for nucleic acids and polypeptides are approximate and are provided for description. Although methods and materials similar or equivalent to those described in this context, can be used when implementing or testing of this description, suitable methods and materials are described below. The term "includes" means "includes". All publications, patent applications, patents, and other references mentioned in this context was introduced by reference in their entirety. In the event of a conflict this description, including explanations of terms that will be used for validation. In addition, the materials, methods and examples are for illustration only and are not intended to limit.

How changes of food intake, appetite, caloric intake and energy expenditure

In this context describes a way to reduce food uptake by peripheral injection to a subject a therapeutically effective amount of PYY or a PYY agonist. In one embodiment, the implementation of the introduction of the PYY or PYY agonist results in lowering the July number or total mass, or total volume of food. In another embodiment, the introduction of PYY or agonist results in reduced absorption of nutrients, such as reducing intake of lipids, carbohydrates, cholesterol or protein. In any of the ways described in this context as a preferred connection can be entered PYY_3-36. This discovery includes the modification of eating behavior and appropriate use of PYY or the agonist for the preparation of a medicinal product for the purposes presented in this context, and includes the use of PYY as a means to reduce the calories, reduce the consumption of food or loss of appetite or increase energy consumption at the subject.

In this context also presents a way to reduce calorie intake by peripheral injection to a subject a therapeutically effective amount of PYY or a PYY agonist. In one embodiment, the implementation of the total calorie intake is reduced by peripheral injection of a therapeutically effective amount of PYY. In other embodiments, the implementation of the reduce calorie intake associated with intake of specific food components, such as, but not limited to, intake of lipids, carbohydrates, cholesterol or protein.

In an additional embodiment, in this context describes the SPO is about reducing appetite by introducing a therapeutically effective amount of PYY or the agonist. Appetite can be measured by any means known to the competent authority in this field. For example, reduced appetite can be defined using psychological assessment. In this embodiment, the introduction of PYY results in a change in the feelings of hunger, satiety and/or satiation. Hunger can be assessed by any means known to the competent authority in this field. In one embodiment, the implementation of the hunger assessed through psychological tests, such as estimating the sensations of hunger and sensory perception, when using the questionnaire, such as, but not limited to, a questionnaire with visual analogue scale (Visual Analog Score, and VAS) (see Examples). In one specific non-limiting example, the hunger assessed by responses to questions relating to desire for food, drinks, the future of food, nausea and the sensation of smell or taste.

In the following embodiment, in this context describes how changes in energy metabolism in the subject. The method includes the peripheral introduction to a subject a therapeutically effective amount of PYY or the agonist to change thus energy costs. The burning of energy occurs in all physiological processes. The body can directly change the cost of energy through the m modulation efficiency of these processes or by changing the number and nature of the ongoing processes. For example, during digestion, the body spends energy on the movement of food through the intestine, as well as the breakdown of food and intracellular processes, and the efficiency of cellular metabolism can be modified to receive more or less heat. In the following embodiment, in this context, the described method of any and all manipulations in the system in the arcuate nucleus submitted with this application, which consistently alter the absorption of food and opposite change energy costs. Energy costs are a result of cell metabolism, protein synthesis, metabolic rate and use calories. Thus, in this embodiment, the peripheral introduction PYY leads to higher energy costs and less efficient use of calories. In one of the embodiments a therapeutically effective amount of PYY or the agonist is administered to a subject to increase thus energy costs.

In some embodiments PYY (e.g., PYY_3-36or its agonist used for weight control, and treatment, reduction or prevention of obesity, in particular, any one or more of the following symptoms: prevention and reduction of weight gain, induction and stimulation of the reduction of body weight and reduce obesity, measured by and the DEXA body mass. In addition, the description concerns the use of PYY or the agonist as an active ingredient in the production of medicines to reduce calorie intake, reduce food intake or reduce appetite or increase energy consumption at the subject. Next description relates to a method of maintaining a desired body weight, maintenance of desired body mass index, desirable appearance and good health with the help of PYY and its agonist.

The subject can be any subject, including humans and mammals objects veterinary medicine. Thus, a subject can be represented by a person or may be a Primate other than humans, agricultural animals such as pig, cattle and poultry, sports animals or Pets, such as dogs, cats, horses, hamsters, rodents, or animals inhabitant of the zoo, such as lions, tigers or bears.

Currently, obesity is difficult to treat, chronic, almost incurable metabolic disorder. Therapeutic drug, is effective in reducing body weight in obese persons, could have a strong positive impact on their health. Thus, a subject can be represented without limitation subject, which is overweight or oiran the E. In one of the embodiments, the subject has or is at risk of developing disorders in which obesity or excessive weight is a risk factor violations. Disorders of interest include, but are not limited to, cardiovascular disease (including, but not limited to, hypertension, atherosclerosis, congestive heart failure, and dyslipidemia), stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as, but not limited to, polycystic ovarian syndrome, cancer (e.g. breast cancer, prostate, colon, endometrial, kidney and esophageal), varicose veins, acanthosis nigricans, eczema, intolerance to physical activity, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, insulin resistance (such as, but not limited to, type 2 diabetes and syndrome X) and thromboembolic disease (see Kopelman, Nature, 404:635-43; Rissanen et al., British Med. J., 301,835, (1990)).

Other associated disorders include depression, anxiety, panic attacks, headaches type migraines, PMS (premenstrual syndrome), chronic pain, fibromyalgia, insomnia, impulsivity, obsessive-compul the extensive disorder and myoclonus. Obesity is a recognized risk factor in terms of increasing the likelihood of complications during General anesthesia (see, e.g., Kopelman, Nature, 404:635-43, (2000)). It reduces life expectancy and carries a serious risk of concomitant diseases of the above.

Other diseases or disorders associated with obesity, are congenital malformations (obesity in the mother is associated with a higher likelihood of neural tube defects), carpal tunnel syndrome (CTS), chronic venous insufficiency (CVI), sleepiness in the daytime, deep vein thrombosis (DVT), end-stage renal disease (ESRD), gout, impaired temperature, disturbances of the immune response, disorders of respiratory function, infertility, liver disease, pain in the lower back, complications during childbirth and gynecological complications, pancreatitis, and abdominal hernia, acanthosis nigricans, endocrine disorders, chronic hypoxia and hypercapnia, dermatological effects, ivory disease, gastroesophageal reflux, heel spurs, swelling of the lower extremities, Mammalia (causing big problems, such as pain from a strapless bra, skin damage, pain in the cervix, the constant smell and infection in skin folds under the breast and so on), a large mass in the anterior abdominal wall (abdominal panniculitis involving frequent is panniculitis, difficulty in walking, frequent infections, odor, difficulty dressing, pain in the lower back), musculo-skeletal disease, pseudotumor brain (or benign intracranial hypertension) and sliding hernia hiatal.

This description of the invention concerns the treatment, prevention, mitigate or alleviate conditions or damage caused, complicated or aggravated due to relatively high nutrient availability. Under "condition or disorder that can be facilitated by reducing the availability of calories (or nutrients)" means any condition or disorder in a subject, which is caused, aggravated or exacerbated due to the relatively high availability of nutrients, or it may be may be alleviated by reducing the availability of nutrients, for example, by reducing the absorption of food. The invention may also be useful for subjects with insulin resistance, glucose intolerance, or have any form of diabetes mellitus (e.g. type 1, 2 or gestational diabetes).

State data or violations constitute violations associated with increased calorie intake, insulin resistance or glucose intolerance, and VK is ucaut, but not limited to, obesity, diabetes, including type 2 diabetes, eating disorders, syndromes of insulin resistance and Alzheimer's disease.

In another embodiment, the subject is a subject who wishes to reduce body weight, such as the subject of the female or male who wants to change her appearance. In yet another embodiment, the subject is a subject who wishes to reduce the feeling of hunger, such as, but not limited to: a person involved in the execution of long-term work that requires a high level of concentration (for example, soldiers on active service, air traffic controllers or truck drivers on long routes and so on).

This invention relates also to method of control of food intake in mammals using PYY or its antagonist. Description of the invention concerns a method of weight control through PYY or its antagonist, in particular, any one or more of the following characteristics: stimulate, facilitate and increase weight gain, reduction, inhibition, and prevention of loss of body weight and increasing body mass, measured by body mass index. In addition, the invention relates to a method of monitoring any one or more of the following characteristics: appetite, satiety and the ode, in particular any one or more of the following characteristics: increase, awakening and stimulation of appetite, reduce, suppress or prevent satiation and satiety and increase stimulation and increased hunger and hunger with the help of PYY or PYY_3-36.

The increased weight may be desirable for commercial reasons in livestock. Thus, you can use PYY antagonist for humans, Pets and other objectively or subjectively valuable animals, such as horses. The PYY antagonists can be used to stimulate appetite and gain weight gain with poor appetite and weight loss or the possibility of its reduction. Specific non-limiting examples include times of illness, the period after accidental injury or injury due to surgical intervention (for example, after burns and, in particular, after severe burns), the recovery period, old age, as well as anorexia and bulimia, and other conditions that cause exhaustion. Stimulation of appetite and increase body weight can be particularly desirable in specific States, for example, cachexia (wasting) in AIDS and cancer patients.

A suitable format introduction can best be defined by the subject or a practical physician. In one embodiment, about what westline pharmaceutical composition, which include PYY or agonist or antagonist, preferably will be prepared in the form of a uniform dosage form, suitable for individual use exact doses. An effective amount of PYY or the agonist can be entered in one dose or in multiple doses, for example daily, during a course of treatment. In one embodiment, the implementation of PYY enter when the desired effect (for example, suppression of appetite, decreased absorption of foods or low calorie intake). In another embodiment, PYY or its analogue is administered shortly before the moment when it is desirable effect, for example, but without limitation, about 10 minutes, approximately 15 minutes approximately 30 minutes approximately 60 minutes approximately 90 minutes approximately 120 minutes prior to the time when the desired effect. In another embodiment, use of time release of the drug.

In one of the embodiments a therapeutically effective amount of PYY or the agonist is administered in a single pulse dose as a bolus dose or as pulse doses, administered over a long period of time. Thus, when pulse doses using a bolus PYY, followed by a period of time in which PYY not introduce the subject, with the subsequent second bolus entered the eating. In specific non-limiting examples, pulse doses of PYY is administered during the day of course, within a week or within a month of the course.

A therapeutically effective amount of PYY or the agonist will depend on the used molecules of the subject, which suggest treating, severity and type of disease and how the introduction. For example, a therapeutically effective amount of PYY or the agonist can vary from about 0.01 microgram/kilogram (kg) of body weight to about 1 g/kg body weight, for example, from about 1 μg to about 5 mg/kg body weight or from about 5 μg to about 1 mg/kg of body weight. In another embodiment, PYY or agonist is administered to a subject at a dose of from 0.5 to 135 picomole (pmol)/kg of body weight or approximately 72 pmol/kg body weight. In one specific non-limiting example, a subcutaneous injection is administered from about 5 to about 50 nmol, for example, from about 2 to about 20 nmol or by subcutaneous injection administered approximately 10 nmol. Competent person skilled in the art will easily determine the dose based on the activity of the specific compound (such as a polypeptide PYY or agonist), age, body weight, gender, and physiological condition of the subject. The dose of the agonist can be molar is equivalent therapeutically effective dose of PYY or PYY _3-36.

The compositions or pharmaceutical compositions may be introduced by any route, including intravenous, intraperitoneal, subcutaneous, sublingual, transcutaneous, intramuscular, oral, outdoor introduction, and introduction through the mucous membranes or pulmonary inhalation. The compositions used in the invention can easily be obtained in the form of preparations suitable for parenteral (including intravenous, intramuscular and subcutaneous), nasal or oral administration. The term "parenteral"as used in this context, relates to methods of introduction, which include intravenous, intramuscular, intraperitoneal, vnutrigrudne, subcutaneous and intraarticular injection and infusion. PYY, including PYY_3-36the agonist PYY or a PYY antagonist, can be administered subcutaneously. In engineering it is well known that subcutaneous injection is easy to do yourself.

In some cases it will be convenient receipt of PYY or PYY agonist and another agent that reduces the absorption of food, reducing the level of glucose in plasma or alter the level of lipids in the plasma, in a single composition or solution for joint injection. In other cases, a better solution is the introduction of an additional agent separately from the specified PYY or a PYY agonist.

A suitable format introduction can be best defined the Yong practical physician individually for each patient. Various pharmaceutically acceptable carriers and their composition are described in the monograph devoted to the standard drugs, for example, Ringtonescom the Handbook of pharmaceutical Sciences (Remington's Pharmaceutical Sciences) edited E.W.Martin. Cm. also Y.J. Wang and M.A. Hanson, Journal of Parenteral Science and Technology, Technical report (Technical Report) No. 10, EXT. 42:2S, (1988).

PYY, PYY agonists and antagonists PYY used in ways that meet this description, can be obtained in the form of parenteral compositions, for example, for injection or infusion. Preferably, when they are suspended in the aqueous medium, for example, in an isotonic buffer solution at a pH of from about 3.0 to about 8.0 a, preferably at pH from about 3.5 to about of 7.4, 3.5 to 6.0, or 3.5 to about a 5.0. Suitable buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid and buffers on the basis of acetate/acetic acid. Can be used with a long action or depo-drug slow release, with a therapeutically effective amount of drug delivered into the bloodstream over many hours or days after percutaneous injection or delivery.

As PYY and agonists are amphoteric, they can be used as free bases, salts formed by addition of acid or Sol is th metals. Of course, the salts should be pharmaceutically acceptable, and they will include metal salts, particularly salts of alkali and alkaline earth metals, for example salts of potassium and sodium. There is a wide range of pharmaceutically acceptable salts obtained by addition of acids. These products can easily be obtained by methods well known to competent specialists in this field.

For use by physicians compositions can be presented in a uniform dosage form containing an amount of PYY or a PYY agonist with or without adding another active ingredient, for example an agent that reduces the absorption of food, reducing the level of glucose in plasma or alter the level of lipids in the plasma. Introduction you can start, when the desired suppression of the availability of nutrients, absorption of food, reduction of body weight, blood glucose or lipids in the plasma, for example, at the first sign of development of symptoms of disorders associated with body weight or soon after diagnosed with obesity, diabetes or syndrome of insulin resistance.

Therapeutically effective amounts of PYY or PYY agonist to reduce the availability of nutrients are the amounts that suppresses appetite to the desired level. As will be obvious to professionals working in this about the region, an effective amount of therapeutic agent will vary depending on many factors, including the activity of the specific compound, the age and body weight of the patient, the physical condition of the patient, the blood sugar level of body weight that you want to receive, and other factors. Similarly, a therapeutically effective amount of PYY antagonist to obtain increase the availability of nutrients are the amounts that increase the appetite to the desired level. As will be obvious to professionals working in this field, an effective amount of this therapeutic agent will vary with many factors, including the activity of the specific compound, the age and body weight of the patient, the physical condition of the patient, the blood sugar level of body weight that you want to receive, and other factors. Introduction you can start, when the desired increased availability of nutrients, food intake, body weight, glucose levels, or reduce the level of lipids in the plasma, for example, but without limitation, at the first sign of development of the symptoms of anorexia or early loss of body weight in AIDS.

The optimal drug and route of administration of PYY, PYY agonists and antagonists PYY patient depends on factors known in the field, that is them as a specific disease or disorders, the desired effect and the type of patient. Although PYY, PYY agonists and antagonists PYY, usually used for treatment of humans, they can also be used to treat similar or identical diseases in other vertebrates, such as other primates, farm animals such as pigs, cattle and poultry, and sports animals and Pets such as horses, dogs and cats.

As a pharmaceutical preparation PYY, PYY agonists and antagonists PYY, corresponding to this invention, can be entered directly by any suitable means, including parenteral, intranasal, oral, or by absorption through the skin. Competitive route of administration of each agent will depend, for example, from the medical history of the animal.

For parenteral administration, in one embodiment, the implementation of PYY, PYY agonists and antagonists PYY can be prepared generally by mixing it at the desired degree of purity in a uniform dosage injectable form (solution, suspension or emulsion) with a pharmaceutically acceptable carrier, i.e. a carrier, which is non-toxic to recipients at the used doses and concentrations, and is compatible with other ingredients of the drug. The term "pharmaceutically acceptable carrier" refers to non-toxic solid, semisolid or liquid filler, the diluent, encapsulating material or secondary drug of any type. For example, preferably, when the drug does not include oxidizing agents and other compounds, known as damaging PYY and PYY agonists.

Typically, the drugs are prepared by homogeneous and close contact PYY, PYY agonist or antagonist PYY with liquid carriers or finely powdered solid carriers or both forms of media. Then, if necessary, from product create a desirable product. Preferably, when the media presents a carrier for parenteral administration, preferably with a solution, isotonic relative to the recipient's blood. Examples of such carriers include water, saline, ringer's solution and dextrose. In addition, in this context, the use of nonaqueous media, such as fatty (non-volatile) oils and etiloleat, and liposomes.

PPY, PYY antagonists and agonists PYY accordingly imposed by systems with a slow release. Examples PYY and PYY agonists delayed release include suitable polymeric materials (such as, for example, semi-permeable polymeric bases in the form of shaped articles, e.g. films, or microcapsules), suitable hydrophobic materials (for example, the emulsion in the reception the reception oil) or ion exchange resins and lahoratories derivatives (as, for example, membrane not easily soluble salt). The composition of the PPY, PYY antagonist and agonist PYY delayed release can be administered orally, rectally, parenterally, intracisternally, vnutrivaginalno, intraperitoneally, topically (e.g., in the form of powders, ointments, gels, drops or transdermal patch), cheek (buccal) or in the form of a spray for the mouth or nose.

Fundamentals of delayed release include polylactide (see U.S. Patent No. 3773919, EP 58481), copolymers of L-glutamato acid and γ-ethyl-L-glutamate (see Sidman et al., Biopolymers, 22:547-556, (1983)), poly-(2-hydroxyethylmethacrylate) (see Langer et al., J. Biomed. Mater. Res., 15:167-277, (1981); Langer, Chem. Tech., 12:98-105, (1982), ethylene vinyl acetate (see Langer et al., id.) or poly-D-(-)-3-hydroxybutiric acid (EP 133988).

PPY, PYY antagonists and agonists PYY delayed release include liposomal PPY and PYY agonists (see main article Langer, Science, 249:1527-1533, (1990); section written by Treat et al. in the monograph "Liposomes in therapy of infectious disease and cancer" ("Liposomes in therapy of Infectious Disease and Cancer") edited by Lopez-Berestein and Fidler, Liss, New York, c.317-327 and 353-365, (1989)). Liposomes containing a peptide and peptide analogues PPY, prepared by methods which are in themselves known (see patent application DE 3218121; articles Epstein et al., Proc. Natl. Acad. Sci. U.S.A., 82:3688-3692, (1985); Hwang et al., Proc. Natl. Acad. Sci. U.S.A., 77:4030-4034 (1980)a; patent application EP 52322, EP 36676, EP 8806, EP 143949, EP 142641, Japanese patent application No. 83-118008; U.S. Patent No. 4485045, U.S. Patent No. 4544545 and patent application EP 102324. Typically, liposomes are presented by the type of the small (about 200-800 angstroms) single layer of liposomes, in which the lipid content of greater than about 30 mol% cholesterol, the selected ratio is adjusted to obtain optimal performance.

Preparations for injection can be prepared accordingly to provide a controlled release of PYY, PYY antagonists and agonists PYY. For example, pharmaceutical compositions can be in the form of particles containing a biodegradable polymer and/or polysaccharide generousity and/or biodegradable polymer, an amphiphilic polymer, an agent that modifies the properties of the section surfaces of the particles and pharmacologically active substance. These compositions exhibit certain properties of biocompatibility, which allow to provide a controlled release of the active substance. Cm. U.S. patent No. 5700486.

In yet another additional embodiment, PPY, antagonists PYY and PYY agonists delivered by a pump (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 14:201, (1987); Buchwald et al., Surgery, 88:507 (1980)a; Saudek et al., N. Engl. J. Med., 321:. 574, (1989)) or by continuous subcutaneous infusions, for example, using Minnesota. Can also be used a tank of Rast is a PR for intravenous injection. A key factor in selecting an appropriate dose is the result obtained, as measured by reduction in total body weight or the ratio of fat and weight that does not contain fat, or other criteria for the determination of the fight or prevent the development of obesity or preventing the development of conditions associated with obesity, which is a practical physician deems appropriate. Other systems with controlled output are discussed in the review Langer (see Science, 249:1527-1533, (1990)).

In another aspect of the invention PPY, PYY antagonists and agonists PYY delivered via an implanted pump is described, for example, in U.S. Patent No. 6436091, U.S. Patent No. 5939380 and U.S. Patent No. 5993414.

Implantable device for infusion of drugs is used to provide patients with permanent long-acting dosage or infusion of drug or other therapeutic agent. In General, such devices can be classified into active and passive.

Active devices for programmable infusion of medicinal substances are characterized by a pump or a metering system that are used for drug delivery system of the patient. An example of such currently available devices for active infusion of medicinal substance is programmable pump Medtronic SynchroMed™. the data pumps, typically include a reservoir for a drug, the peristaltic pump for pumping the drug from the reservoir and opening for the catheter to transfer deflated by a pump drugs from the reservoir into the patient. These devices typically have a battery to power the pump, and an electronic module for controlling the flow rate provided by the pump. Pump Medtronic SynchroMed™, in addition, includes an antenna for remote programming of the pump. In contrast, passive devices for infusion of drugs do not have a pump, but the basis of their action is the tank with medication under pressure, which delivers drugs. Thus, these devices are usually smaller and cheaper than active devices. An example of such a device includes Medtronic IsoMed™. This device delivers medicinal substance to a patient by force, which gives the tank under pressure, is connected through the control unit of the stream.

The implanted pump can be completely implanted under the skin of the patient, thereby eliminating the necessity of using subcutaneous catheter. Data implanted pumps can provide the patient PYY, a PYY antagonist or agonist PYY with constant or programmable speed picking and, for example, to give a pulse dose during the meal or around that time. The fixed speed pumps or programmable speed based on either phase change or peristaltic technology. When you want a permanent unchanging speed of delivery, the fixed speed pumps are well suited for implantable delivery system of long-term medication. If you anticipate a change in the speed of diffusion, it is possible to use the programmable pump system instead of fixed speed pumps. Osmotic pumps are much less than other pumps with constant speed or programmable pumps, because the infusion rate can be very low. An example of such a pump is shown in U.S. Patent No. 5728396.

When administered orally, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by accepted means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-klasterizovannykh corn starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, microcrystalline cellulose or acidic calcium phosphate); moving components (e.g., magnesium stearate, talc or silica); desintegra components (in the example, potato starch or glycolate starch sodium) or moisturizing agents (e.g. sodium lauryl sulphate). Tablets can be coated with use of methods that are well known in the art. Liquid preparations for oral administration can, for example, take the form of solutions, syrups or suspensions, or may be presented in a dry product for restore water or other suitable vehicle before use. Data liquid preparations can be prepared by accepted methods using pharmaceutically acceptable additional components, such suspendresume agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or gum Arabic); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid). Needed preparations may also contain buffer salts, flavoring components, colorants and sweeteners.

For administration by inhalation the compounds used according to this invention, conveniently delivered in the form of an aerosol, presents the packages under pressure or spray using suitable propellant, in the example, DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure, the unit dosage will determine if using a valve that delivers a measured amount. For use in inhaler or device for injection may be prepared with capsules and cartridges of, for example, from gelatin containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

Compounds can also be prepared in the form of rectal compositions such as suppositories or enemas with slow action, for example, containing the accepted bases for suppositories, such as cocoa butter or other glycerides.

In addition to the above compounds, the compounds may be prepared as depot preparations. These drugs for long periods can be introduced by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. For example, the compounds may be prepared in combination with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion with an acceptable oil) or ion exchange resins, or as membrane not easily soluble derivatives, for example membrane not easily soluble salts.

In the formulation of pharmaceutical compositions, which as the active agent content is t PYY, or its agonist, or antagonist, PYY, as described in this context, you will usually enter the appropriate solid or liquid carrier, depending on the selected specific way of introduction. Pharmaceutically acceptable carriers and excipients used in this description of the invention, are conventional. For example, parenteral preparations usually contain injectable fluids that are pharmaceutically and physiologically acceptable liquid carriers such as water, saline, other balanced salt solutions, aqueous dextrose, glycerol and the like, Fillers that can be included, represented, for example, other proteins such as human serum albumin or plasma preparations. If desired, the pharmaceutical composition intended for the introduction, can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, preservatives and agents, sautereau pH and the like, for example sodium acetate or sorbitanoleat. You can also enter other medical and pharmaceutical agents, for example other components that suppress the appetite, or protease inhibitors. Competent specialists in this field are known or will be apparent modern methods need a kitchen the population data of dosage forms.

Dosage form of the pharmaceutical composition will be determined by the selected method of administration. For example, in addition to injecting fluids can be used inhaled forms, suppositories and oral medications. The pharmaceutical compositions can be prepared using accepted processes of mixing, granulating, mixing with honey or syrup, dissolution or lyophilization.

Oral drugs may be liquid (e.g., syrups, solutions or suspensions) or solid (e.g., powders, pills, tablets or capsules). For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with one or more solid carriers, optionally granulating the resulting mixture and, if desired, processing the mixture or granules, if necessary, introduce additional excipients to form tablets or cows bean.

Suitable carriers include fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations of cellulose and/or calcium phosphates, for example tricalcium phosphate or calcium phosphate, and also binders components such as starches, for example corn, wheat or potato starch, methylcellulose, hypromellose, carboxine is cellulose sodium salt and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the abovementioned starches, cross-linked polyvinylpyrrolidone, alginic acid or its salt, such as sodium alginate. Additional fillers include agents, conditioning fluidity and lubricity components, for example silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium and/or polyethylene glycol or its derivatives.

Compositions for parenteral administration include suitable aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or aqueous injection suspensions that contain substances that modify the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and, if desired, stabilizers. The active ingredient optionally together with fillers may also be in the form of freeze-dried and can be converted into a solution prior to parenteral introduction by the addition of suitable solvents. Such solutions, as, for example, are used for parenteral administration, can be used as infusion solutions.

Inhalation PYY or the agonist, or antagonist of PYY is administered in the form of a spray or dispersion media. In one specific non-limiting example, the PYY or agonist is administered in Aero the OLE out of the ordinary valve, such as, but not limited to, metering valve, through aerosol adapter, also known as a regulating valve. The drug may also be introduced suitable liquid carrier, such as, but not limited to, air, hydrocarbons, including n-butane, propane, isopentane and others, or propellant, such as, but not limited to, fluorocarbon. Optional, but may also be introduced stabilizer and/or for deep delivery to the lungs can be included porous particles (for example, see U.S. Patent No. 6447743).

To obtain preparations of compounds with poor solubility in aqueous systems requires the use solubilizing agents, such as ionic surfactants, holty, polyethylene glycol (PEG), ethanol and other agents that may cause adverse effects when used for inhalation. Furthermore, treatment, requiring effective delivery to the alveoli of the lower lobes of the lung, may prevent the use in the preparation of some annoying features, such as chlorofluorocarbons, and it should include the minimum number of required doses. Alternatively, to avoid this limitation, you can use liposomes or hydrophobic particles. In one of the embodiments of the aerosol drug delayed release of Navan on the use of aerosol droplet particle size of about 1-2,1 micron or smaller than 1 μm. Small aerosol particles of liposomes and combinations of liposomes and drug substances for use in medicine described previously (for example, see patent application EP 87309854.5).

In one of the embodiments a therapeutically effective amount of PYY or the agonist is administered with a therapeutically effective amount of another agent, such as, but not limited to, additional agent that suppresses appetite. Specific non-limiting example of an additional agent that suppresses appetite, includes amfepramone (diethylpropion), phentermine, mazindol and phenylpropanolamine, fenfluramine, dexfenfluramin and fluoxetine. PYY and/or PYY agonist can be administered simultaneously with an additional agent, overpowering appetite or they can be entered sequentially. Thus, in one embodiment, the implementation of PYY is prepared and injected with the agent, the overwhelming appetite, as a single dose.

Additionally, in this context, describes a method for the treatment of obesity. The method comprises the administration to a subject with obesity therapeutically effective amount of PYY or a PYY agonist. Agonist PYY may have activity, which at least in one aspect, the absorption of food or gastric emptying exceeds the activity of NPY. PYY and/or PYY agonist can be entered perifericheskie, for example, in a single or divided dose. Suitable hotel is or divided doses include, but not limited to from 1 µg to about 5 mg or about 0.01 μg/kg to about 500 μg/kg/dose. The subject can have insulin resistance or glucose intolerance, or have both disorders. In addition to obesity, the subject may suffer from diabetes.

A method of reducing the absorption of food is also described in this context. The method comprises the administration to a subject with obesity therapeutically effective amount of PYY or a PYY agonist. Agonist PYY may have activity, which at least in one aspect, the absorption of food or gastric emptying exceeds the activity of NPY. PYY and/or PYY agonist can be entered perifericheskie, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to, from 1 μg to about 5 mg or about 0.01 μg/kg to about 500 μg/kg/dose. The subject may suffer from type II diabetes or to be overweight.

In this context, describes a method of improving the lipid profile of a subject. The method includes introducing to a subject an effective amount of PYY or a PYY agonist. Improvement of lipid profile includes, but without limitation, at least one aspect of lowering cholesterol, lowering levels of triglycerides and increased levels of HDL-x is Listerine (cholesterol, containing high-density lipoproteins). PYY and/or PYY agonist can be entered perifericheskie, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to from 1 µg to about 5 mg or about 0.01 μg/kg to about 500 μg/kg/dose. Agonist PYY may have activity, which at least in one aspect, the absorption of food or gastric emptying exceeds the activity of NPY.

In another embodiment, in this context, describes a method of facilitating conditions or disorders which can be alleviated by reducing the availability of nutrients. The method includes introducing to the subject a therapeutically effective amount of PYY or a PYY agonist. The irregularities include any of the above violations. PYY and/or PYY agonist can be administered perifericheskie, for example, in a single or divided dose. Suitable single or divided doses include, but are not limited to from 1 µg to about 5 mg or about 0.01 μg/kg to about 500 μg/kg/dose. Agonist PYY may have activity, which at least in one aspect, the absorption of food or gastric emptying exceeds the activity of NPY. Suitable doses include doses that increase the concentration of PYY and/or it is agonist significantly higher baseline concentrations of PYY, such as, but not limited to, dose, mimic the concentration of PPY (or agonist) in serum after ingestion. Thus, in one embodiment, the implementation of the PYY or agonist is administered to achieve or obtain the effect of reducing calorie intake, food intake, or appetite, is equal to the reduction in calorie intake, food intake or appetite or increase energy expenditure caused by the level of PYY_3-36that occurs after a meal. Specific non-limiting examples of dosages include, but are not limited to, dose that give the effect shown when serum levels of PYY are from about 40 PM to about 50 PM or from about 40 PM to about 45 PM or up to approximately 43 PM.

For all methods described in this context, the dose of PYY or PYY_3-36can be based on physiological levels observed after a meal. Normal levels of PYY_3-36in the circulatory system account for approximately 8 pmol/l, typically up to about 40 to 60 pmol/l after a meal. PYY agonists can be used in similar doses. A single dose may be administered once a day or can be used in divided doses (see above). Since it was shown that PYY_3-36effective up to 12 and even up to 24 hours after administration,with the possible introduction of only two or even only once per day.

In one of the embodiments with the peripheral introduction PYY, including PYY_3-36shows the effects on the physiological levels. Other intestinal hormones (e.g., GLP) with the peripheral introduction show the effect only at levels above the physiological and have side effects. When using PYY3-36 side effects not see. Regardless of theory, PYY_3-36not valid for Y2 receptors in the brain, which could cause side effects. Without limitation, it should be noted that another advantage PYY_3-36is that PYY_3-36does not increase blood pressure. The effects of PYY_3-36are long and be 24 hours. Described that the recipients have noted a decline in appetite during this period and the reduction of food intake by approximately one third.

In one specific non-limiting example, PYY_3-36administered at a dose of approximately 1 nmol or more, 2 nmol or more, or 5 nmol or more. In this example, the dose of PYY_3-36as a rule, does not exceed 100 nmol, for example the dose of 90 nmol or less, 80 nmol or less, 70 nmol or less, 60 nmol or less, 50 nmol or less, 40 nmol or less, 30 nmol or less, 20 nmol or less, 10 nmol. For example, the dosage interval may contain any combination of any of the limits specified over the izkuyu doses with any limits specified higher doses. Thus, an exemplary non-limiting intervals doses include the dose of PYY_3-36that may be in the range from 1 to 100 nmol, from 1 to 90 mole, from 1 to 80 nmol. Exemplary non-limiting intervals doses comprise from 2 to 100 nmol, from 2 to 90 nmol, for example from 2 to 80 nmol etc., from 5 nmol to 100 mol, from 5 to 90 nmol nmol, 5 nmol to 80 nmol etc. Example of dose that can be administered is a dose of from about 5 to about 50 nmol, such as, but not limited to, from about 2 to about 20 nmol, for example approximately 10 nmol. The selected dose may be entered, for example, by injection, in particular in the form of a subcutaneous injection. In one embodiment, the implementation of the injected dose of PYY or PYY_3-360,143 nmol (1/7 mol/kg to achieve a dose similar to that of PYY level after a meal.

When using the PYY or the agonist dose preferably represents a molar equivalent dose of PYY_3-36as explained above. The dose can be calculated according to subject, such as a subject with a body weight of 70 to 75 kg Competent specialist in this area is easy to determine the exact dose based on the activity of the specific compound (such as a polypeptide or agonist PYY), as well as age, body weight, gender, and physiological condition of the subject.

As shown in D. Nam context, natural peptide, PYY or PYY_3-36can be used to achieve a physiological effect. This results in minimal side effects and, if necessary, provides a long lasting effect. Dose of PYY or PYY_3-36can be based on physiological levels observed after a meal. Normal levels of PYY_3-36in the circulatory system account for approximately 8 pmol/l, typically up to about 40 to 60 pmol/l after a meal. PYY (e.g., PYY_3-36and agonists can be used in similar doses.

So, different ways of applying the PYY or agonist or antagonist, as described above, may be used in the method of treatment of a mammal subject, which requires this treatment, or can be represented in the production of drugs for such treatment. PYY (e.g., PYY_3-36or its agonist, or antagonist should be entered in the amount effective to achieve the stated object. Some of these solutions are methods of treatment, such as treatment of obesity. However, other solutions do not relate to the treatment and are part of maintaining a healthy lifestyle or are used for cosmetic purposes.

PYY agonists

The PYY agonist used in the methods corresponding to this invention, the pre is is a molecule, which binds to a receptor that specifically binds a PYY and determines the effect of PYY. In the field of engineering known methods of analysis of binding with receptors PYY and receive the response in a cell with a PYY receptor. Specific analysis aimed at the detection of a PYY agonist, is presented in this context. So, in one of the embodiments, the PYY agonist is associated with neurons containing NPY in the arcuate nucleus that results electrophysiological effect on neurons containing NPY. As presented in this context, forms a synapse with neurons O.G. ROMs. Thus, the electrophysiological effect on neurons containing NPY, can cause further electrophysiological effect on neuron O.G. ROMs. In one specific non-limiting examples of the introduction of PYY agonist results in the hyperpolarization of the membrane potential of a neuron O.G. ROMs. In another specific non-limiting example, the introduction of a PYY agonist increases IPSCs in neurons O.G. ROMs.

In another embodiment, the PYY agonists do not include NPY. Suitable PYY agonists represented by molecules that bind neurons containing NPY, but not pass through the blood-brain barrier. Neurons in the arcuate nucleus, which acts PYY not protected by the blood-brain barrier, and vsledstvii is that they are easily accessible for perifericheskie input molecules. In addition, other brain regions that Express the receptor Y2, protected by the blood-brain barrier. Regardless of theory, the agents are able to communicate with Y2R arcuate nucleus, but does not cross the blood-brain barrier after peripheral injection are probably effective.

In one of the embodiments, the PYY agonist is a compound that affects the absorption of food, calorie intake, or appetite and/or which specifically binds to the analysis using receptor Y or competes for binding with PYY, as in the analysis of competitive binding using labeled PYY. PYY agonists include, but are not limited to, compounds that bind to the Y2 receptor.

PYY and agonists used in the methods described in this context include, but are not limited to, polypeptides that contain or, alternatively, consisting of amino acid sequence PPY and its agonists, such as their mutants, inversion, fragments and/or variants. Variants include deletions, insertions, inversions, repeats, and substitutions, such as conservative substitutions and non-conservative substitutions (see, for example, Tables 1 and 2 below). More than one amino acid (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 etc) can be removed, or introduced or replaced by another amino acid is the same. Typically, conservative substitutions are substitution of one amino acid to another, among the aliphatic amino acids Ala, Val, Leu and Il; the interchange of Ser and Thr, containing hydroxyl residues, the interchange of the acidic residues Asp and Glu, the interchange among the amide residues Asn and Gln, exchange of the basic residues Lys and AGD, the interchange of aromatic residues Phe and Tight and the exchange of amino acids of a small amount of Ala, Ser, Thr, Met, and Gly. Guidance concerning how to make phenotypically silent substitutions of amino acids shown in Bowie et al., Science, 247:1306-1310, (1990).

As another example, polypeptide fragments can contain a continuous series of deleted residues from the amino (N)or carboxyl (C)-end, or both ends (see, for example, Tables 1 and 2 below). From the N-Terminus, the C-end, or both ends may be removed by any number of amino acids in the range from 1 to 24.

Furthermore, agonistic polypeptides may also include, but not limited to, polypeptides that contain or, alternatively, consisting of internal deletions of the amino acid sequence PPY and/or its agonists (see, for example, Tables 1 and 2 below). These deletions can be represented by deletions of one or more amino acid residues (e.g., one, two, three, four, five, six, seven, eight, nine, ten and so on) and can start Atisa with any provision of amino acids (for example, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, and so on). In addition, the polypeptides corresponding to this description of the invention may contain one or more internal deletions. Data deletion is possible in PPY, NPY and PP.

Also consider agonistic peptides presented chimeras PPY, NPY and/or PP, which have high affinity and/or selectivity in respect of the Y2 receptor. These chimeras can contain substitutions of amino acids of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 etc.) of PPY, NPY and/or PP, variants, mutants, and/or deletions of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 etc) from the second PPY, NPY or PP, variants, mutants, and/or deletions. Data replacement can begin with the provisions of any amino acid (e.g., second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, and so on).

Preferably, when the peptide has a selectivity in relation to the Y2 receptor. This means that it binds to the Y2 higher affinity compared with other receptors, such as Y1, Y2, Y3, Y4, Y5 and Y6. In another embodiment, the peptide has a selectivity of receptor Y2 and Y5 relatively receptors Y1, Y3, Y4 and Y6.

Other polypeptide fragments are fragments containing structure is RNA or a functional domain of the polypeptide, match the description of the invention. These fragments include amino acid residues that contain spiral polyproline type II (residues 1-8), β-fold (residues 9-14), amphipatic α-helix (residues 15-32) and/or structure of the C-terminal fold (residues 33-36). Cm. article Kirby et al., J. Med. Chem., 36:385-393, (1993).

In addition, this description of the invention includes the use of the polypeptide or agonist containing or, alternatively, consisting of amino acid sequence species variants PPY, NPY and PP (see Table 1 below) and/or their mutants and fragments.

Also discussed fused proteins, where PYY or PYY agonist is fused with another protein or polypeptide (a merge partner) using recombinant methods known in the art. Alternative such a protein can be obtained by synthesis using any known method. As a partner of the merge can be used any known peptide or protein (such as serum albumin, coal kind Midrash, glutathione S-transferase or thioredoxin etc). Preferred partners merger will not possess the harmful biological activity in vivo. These partners merge can be constructed by binding of the carboxy-end of a merge partner with aminocom.com peptide PYY or agonist or Vice versa. Optional can be used for sovan linker split plot, connecting the PYY or PYY agonist with a merge partner, and it can be derived in vivo, which could lead to the exit of the active forms of PYY or a PYY agonist. Examples of data cleavage sites include, but are not limited to, the linker sections D-D-D-D-Y (SEQ ID NO:330), G-P-R (SEQ ID NO:331), A-G-G (SEQ ID NO:332) and H-P-F-H-L (SEQ ID NO 333), which can split enterokinase, thrombin, ubiquitin-rossemaison enzyme and renin, respectively. See, for example, U.S. Patent No. 6410707.

In addition, as considered effective PYY agonists represented by Y2-specific peptide NPY agonists, as described in U.S. Patent No. 5026685, U.S. Patent No. 5574010, U.S. Patent No. 5604203, U.S. Patent No. 5696093, U.S. Patent No. 6046167. (See below).

Preferred agonists PPY described in this context as follows.

Cm. article Beck-Sickinger A.G., Jung G., Biopolymers (Biopolymers), 37:123-142, (1995).

IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO:334)

Reference: see Eberlein et al., Peptides, 10:797-803, (1989), Grandt et al., Peptides, 15(5):815-20, (1994).

Variations PPY (3-36)

N-terminal deletions PYY, including without limitation: PYY(26-36), PYY(25-36), PYY(24-36), PYY(23-36), PYY(22-36), PYY(21-36), PYY(20-36), PYY(19-36), PYY(18-36), PYY(17-36), PYY(16 to 36), PYY(15-36), PYY(14-36), PYY(13-36), PYY(12-36), PYY(11-36), PYY(10-36), PYY(9-36), PYY(8-36), PYY(7-36), PYY(6-36), PYY(5-36), PYY(4-36), PYY(3-36).

Reference: See for example, article Balasubramaniam et al., Pept. Res. 1(1):32-5, (Sept.-Oct. 1998); Liu et al., J. Gastrointest. Surg., 5(2):147-52, (March-April 2001).

The peptide Sequence

NPY (human)

YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO:2)

Reference: see Tatemoto et al., Proc. Natl. Acad. Sci. U.S.A., 79:5485-9, (1982).

Variations NPY

N-terminal deletions NYY, including, but not limited to: NPY(26-36), NPY(25-36), NPY(24-36), NPY(23-36, NPY(22-36), NPY(21-36), NPY(20-36), NPY(19-36), NPY(18-36), NPY(17-36), NPY(16 to 36), NPY(15-36), NPY(14-36), NPY(13-36), NPY(12-36), NPY(11-36), NPY(10-36), NPY(9-36), NPY(8-36), NPY(7-36), NPY(6-36), NPY(5-36), NPY(4-36), NPY(3-36).

Reference: see, for example, articles Gehlert et al., Proc. Soc. Exp.Biol. Med., 218: 7-22, (1998); Sheikh et al., Am. J. Physiol., 261:0701-15, (November 1991).

Internal deletions, including without limitation: (1-4)-Aca-(14-36)pNPY, (1-4)-Aca-(15-36)pNPY, (1-4)-Aca-(16 to 36)]pNPY, (1-4)-Aca-(17-36)pNPY, (1-4)-Aca-(18-36)pNPY, (1-4)-(31-36)pNPY11, (1-4)-Aca-(31-36)pNPY, (4-1)-(31-36)pNPY, (4-1)-Aca-(31-36)pNPY, (4-1)D-(31-36)pNPY, (4-1)D-Aca-(31-36)pNPY.

Reference: see Fournier et al., Mol. Pharmacol., 45(1):93-101, (Jan. 1994).

Additional internal deletion mutants, including without limitation: des-AA^10-17-NPY, des-AA^10-17Ac-[D-Lys⁹(∈-Ac-Ala)]NPY, des-AA^10-17Ac[D-Lys⁹[∈-Ac-Ala)]NPY, des-AA^10-17[Ala^7,21]NPY, des-AA^10-17[Cys^7,21]NPY, des-AA^10-17[Glu⁷,Lys²¹]NPY, [des-AA^11-17[D-Lys¹⁰(∈-AC), Cys^7,21]NPY, des-AA^10-17[D-Cys⁷,D-Lys(∈-Ac),Cys²¹]NPY, des-AA^10-17[D-Cys⁷,Lys⁹(∈-Ac),Cys²¹]NPY, des-AA^10-17[Cys^7,21Pro³⁴]NPY, des-AA^10-17[Asp⁷,Dpr²¹Pro³⁴]NPY, des-AA^10-17[Glu⁷,Lys²¹Pro³⁴]NPY, des-AA^10-17[Cys^7,21,Leu³¹Pro³⁴]NPY, des-AA^10-20[ys^7,21The EMG³⁴]NPY, des-AA^10-17[Cys^2,27]NPY, des-AA^10-17[Cys², D-Cys²⁷]NPY.

Reference: see Kirby et al., J. Med. Chem., 38:4579-86, (1995).

Cyclizes is d agonist NPY, including without limitation: [Lys25-Glu29]NPY(Ac-25-36), [Glu25-Lys29]NPY(Ac-25-36), [Lys26-Glu31] NPY(Ac-25-36), [Glu27-Lys31]NPY(Ac-25-36), [Lys28-Glu32]NPY(Ac-25-36), [Lys27-Glu34]NPY(Ac-25-36).

Reference: see Rist et al., Eur. J. Biochem. 247:1019-1028, (1997).

Replacement of D-amino acids: [D-Tyr¹]NPY, [D-Pro²]NPY, [D-Ser³]NPY, [D-Lys⁴]NPY, [D-Pro⁵]NPY, [D-Asp⁶]NPY, [D-Asn⁷]NPY, [D-Pro⁸]NPY, [D-Ala⁹]NPY, [D-Glu¹⁰]NPY, [D-Asp¹¹]NPY, [D-Ala¹²]NPY, [D-Pro¹³]NPY, [D-Ala¹⁴]NPY, [D-Glu¹⁵]NPY, [[D-Asp¹⁶]NPY, [D-Leu¹⁷]NPY, [D-Ala¹⁸]NPY, [D-Arg¹⁹]NPY, [D-Tyr²⁰]NPY, [D-Tyr²¹]NPY, [D-Ser²²]NPY, [D-Ala²³]NPY, [D-Leu²⁴]NPY, [D-Arg²⁵]NPY, [[D-His²⁶]]NPY, [D-Tyr²⁷]NPY, [D-Ile²⁸]NPY, [D-Asn²⁹]NPY, [D-Leu³⁰]NPY, [D-Ile³¹]NPY, [D-Thr³²]NPY, [D-Arg³³]NPY, [D-Gln³⁴]NPY, [D-Arg³⁵]NPY, [D-Tyr³⁶]NPY, [D-Tyr¹D-Pro²]NPY, [D-Ser³,D-Lys⁴]NPY, [D-Pro⁵,D-Asp⁶]NPY, [D-Asn⁷D-Pro⁸]NPY, [D-Glu¹⁰,D-Asp¹¹]NPY, [D-Asp¹¹,D-Ala¹²]NPY, [D-Pro¹³,D-Ala¹⁴]NPY, [D-Glu¹⁵,D-Asp¹⁶]NPY, [D-Met¹⁷,D-Ala¹⁸]NPY, [D-Arg¹⁹,D-Tyr²⁰]NPY, [D-Tyr²¹,D-Ser²²]NPY, [D-Ala²³,D-Leu²⁴]NPY, [D-Arg²⁵,D-His²⁶]NPY, [D-Tyr²⁷,D-Ile²⁸]NPY, [D-Asn²⁹,D-Leu³⁰]NPY, [D-Ile³¹,D-Thr³²]NPY, [D-Arg³³,D-Gln³⁴]NPY, [D-Arg³⁵,D-Tyr³⁶]NPY.

Reference: see Kirby et al., J. Med. Chem., 36:3802-08, (1993);

Grundemar et al., Regulatory Peptides, 62:131-136, (1996).

the other agonists and analogs of NPY

The peptide Sequence

NPY(3-36)

SKPDNPGEDAPAEDMARYYSALRHYINLITRQRY (SEQ ID NO:335)

Reference: see Grandt et al., Regulatory Peptides, 67(1):33-7, (1996).

The peptide Sequence

N-Acetyl NPY(24-36)

LRHYINLITRQRY (SEQ ID NO:213)

Reference: see Potter et al., Eur. J. Pharmacol. 267(3):253-262, (17 may 1994).

The peptide Sequence

N-Acetyl [Leu²⁸,Leu³¹]NPY(24-36)

LRHYLNLLTRQRY (SEQ ID NO:214)

Reference: see Potter et al., Eur. J. Pharmacol. 267(3):253-262, (17 may 1994).

The peptide Sequence

[Leu²⁸,Leu³¹]NPY(24-36)

LRHYLNLLTRQRY (SEQ ID NO:215)

Reference: see Potter et al., Eur. J. Pharmacol. 267(3):253-262, (17 may 1994).

The peptide Sequence

[Leu¹⁷,Gln¹⁹Ala²¹Ala²²Glu²³,Leu²⁸,Leu³¹]NPY(13-36)

PAEDLAQYAAELRHYLNLLTRQRY (SEQ ID NO:216)

Reference: see Potter et al., Eur. J. Pharmacol. 267(3):253-262, (17 may 1994).

The peptide Sequence

Cyclo S-S [Cys²⁰,Cys²⁴]pNPY

SKPDNPGEDAPAEDMARCysACRHYINLITRQry (SEQ ID NO:315)

Reference: see Soil et al., Eur. J. Biochem., 268(10):2828-37, (may 2001).

The peptide Sequence

Cyclo-(28/32)-Ac-[Lys²⁸-Glu³²]-(25-36)-pNPY

RHYLNLIGRQRY (SEQ ID NO:316)

Reference: Cabrele et al., J. Pept. Sci., 6(3):97-122, (March, 2000)

The peptide Sequence

Cyclo-(27/31)-Ac-[Glu²⁷-Lys³¹]-(25-36)-pNPY]

RHGLNLLGRQRY (SEQ ID NO:317)

Reference: Cabrele et al., J. Pept. Sci., 6(3):97-122, (March, 2000)

The peptide Sequence

[Tyr³²,Leu³⁴]NPY(27-36)

Reference: see Leban et al., J. Med. Chem., 38:1150-57, (1995).

The peptide Sequence

[Tight³²,Leu³⁴]NPY(26-36)

HYINLIYRLRY (SEQ ID NO:319)

Reference: see Leban et al., J. Med. Chem., 38:1150-57, (1995).

The peptide Sequence

[Tight³²,Leu³⁴]NPY(25-36)

RHYINLIYRLRY (SED ID NO:320)

Reference: see Leban et al., J. Med. Chem., 38:1150-57, (1995).

The peptide Sequence

[Leu³¹]NPY(27-36)

YINLLYRQRY (SEQ ID NO:321)

Reference: see Leban et al., J. Med. Chem., 38:1150-57, (1995).

The peptide Sequence

[Tight³²,Leu³⁴](1-4)-Ahr-(27-36)NPY

YPSL-Aha-YINLIYRLRY (SED ID NO:322)

Reference: see Leban et al., J. Med. Chem., 38:1150-57, (1995).

The peptide Sequence

[Tight³²,Leu³⁴]NPY(28-36)

INLIYRLRY (SEQ ID NO:323)

Reference: see Leban et al., J. Med. Chem., 38:1150-57, (1995).

The peptide Sequence

PP(man)

ASLEPEYPGDNATPEQMAQYAAELRRYINMLTrpry (SEQ ID NO:3)

Reference: see Kimmel et al., Endocrinology, 83:1323-30, (1968).

Variations RR

N-terminal deletions including without limitation: PP(26-36), PP(25-36), PP(24-36), PP(23-36), PP(22-36), PP(21-36), PP(20-36), PP(19-36), PP(18-36), PP(17-36), PP(16 to 36), PP(15-36), PP(14-36), PP(13-36), PP(12-36), PP(11-36), PP(10-36), PP(9-36), PP(8-36), PP(7-36), PP(6-36), PP(5-36), PP(4-36), PP(3-36).

Point mutations of PYY(24-36)

As mutations of PYY(24-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of the C data of the three mutants with any of the above mutants PYY(25-36), for example, [Lys²⁵]PPY(24-36) (Sequence aminocyclo=LKHYLNLVTRQRY (SEQ ID NO:191)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:145.

Point mutations of PYY (23-36)

As mutations of PYY(23-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(24-36), for example, [Lys²⁵]PPY(23-36) (amino acid Sequence=SLKHYLNLVTRQRY (SEQ ID NO:192)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:148.

Point mutations of PYY(22-36)1

As mutations of PYY(22-36) also includes variations of the polypeptides (variations placentas is Teleostei amino acids), the resulting combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(23-36), for example, [Lys²⁵]PPY(22-36) (amino acid Sequence=ASLKHYLNLVTRQRY (SEQ ID NO:193)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:150.

Point mutations of PYY(21-36)

As mutations of PYY(21-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of any of these three mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(22-36), for example, [Lys²⁵]PPY(21-36) (amino acid Sequence=YASLKHYLNLVTRQRY (SEQ ID NO:194)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:152.

Point mutations of PYY(20-36)

As mutations of PYY(20-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of any of these three mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(21-36), for example, [Lys²⁵]PPY(20-36) (amino acid Sequence=YYASLKHYLNLVTRQRY (SEQ ID NO:195)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:155.

Point mutations of PYY(19-36)

As mutations of PYY(19-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(20-36), for example, [Lys²⁵]RDD(19-36) (Sequence is alnost amino acids=RYYASLKHYLNLVTRQRY (SEQ ID NO:196)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:158.

Point mutations of PYY(18-36)]

As mutations of PYY(18-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(19-36), for example, [Lys²⁵]PPY(18-36) (amino acid Sequence=NRYYASLKHYLNLVTRQRY (SEQ ID NO:197)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:160.

Point mutations of PYY(17-36)

As mutations of PYY(17-36) also includes variations of the polypeptides (variations in amino acid sequence), about azusena as the result of a combination of any of these three mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(18-36), for example, [Lys²⁵]RDD(17-36) (amino acid Sequence=LNRYYASLKHYLNLVTRQRY (SEQ ID NO:198)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:162.

Point mutations of PYY(16 to 36)

As mutations of PYY(16 to 36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(17-36), for example, [Lys²⁵]PPY(16 to 36) (amino acid Sequence=ELNRYYASLKHYLNLVTRQRY (SEQ ID NO:199)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:165.

Point mutations of PYY(15-36)

As mutations of PYY(15-36) are also included variations polypep the Dov (variations in amino acid sequence), the resulting combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(16 to 36), for example, [Lys²⁵]PPY(15-36) (amino acid Sequence=EELNRYYASLKHYLNLVTRQRY (SEQ ID NO:200)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:167.

Point mutations of PYY(14-36)

As mutations of PYY(14-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of this mutant with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(15-36), for example, [Lys²⁵]PPY(14-36) (amino acid Sequence=PEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:201)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:169.

Point mutations of PYY(13-36)

In the when asked mutations of PYY(13-36) also includes variations of the polypeptides (variations in amino acid sequence), the resulting combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(14-36), for example, [Lys²⁵]RDD(13-36) (amino acid Sequence=SEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:202)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:170.

Point mutations of PYY(12-36)

As mutations of PYY(12-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(13-36), for example, [Lys²⁵]PPY(12-36) (amino acid Sequence=ASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:203)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:172.

Point mutations of PYY(11-36)

As mutations of PYY(12-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(12-36), for example, [Lys²⁵]PPY(11-36) (amino acid Sequence=DASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:204)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:174.

Point mutations of PYY(10-36)

As mutations of PYY(10-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(11-36), for example, [Lys²⁵]PPY(10-36) (Sequence of aminocell=EDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:205)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:176.

Point mu is then PYY(9-36)

As mutations of PYY(9-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of this mutant with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(10-36), for example, [Lys²⁵]PPY(9-36) (amino acid Sequence=GEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:206)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:178.

Point mutations of PYY(8-36)

As mutations of PYY(8-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of this mutant with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(9-36), for example, [Lys²⁵]PPY(8-36) (amino acid Sequence=SEQ ID NO:207)) is formed by combining mutations of SEQ ID NO: 36 to SEQ ID NO:179.

Point mutations of PYY(7-36)

As mutations of PYY(7-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(8-36), for example, [Lys²⁵]PPY(7-36) (amino acid Sequence=APGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:208)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:180.

Point mutations of PYY(6-36)

As mutations of PYY(6-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these two mutants with any of the above mutants PYY(25-36), and/or any of the above is utanov PYY(7-36), for example, [Lys²⁵]RDD(6-36) (amino acid Sequence=EAPGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:209)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:182.

Point mutations of PYY(5-36)

As mutations of PYY(5-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of this mutant with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(6-36), for example, [Lys²⁵]PPY(5-36) (amino acid Sequence=PEAPGEDASPEELNRYYASLKHYLNLVTRQRY SEQ ID NO:210)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:184.

Point mutations of PYY(4-36)

As mutations of PYY(4-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from a combination of any of these four mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(5-36), for example, [Lys²⁵]PPY(4-36) (amino acid Sequence=KPEAPGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:211)) is formed by combining mutations of SEQ ID NO:36 to SEQ ID NO:185.

Point mutations of PYY(3-36)

As mutations of PYY(3-36) also includes variations of the polypeptides (variations in amino acid sequence), resulting from the combination of any of these three mutants with any of the above mutants PYY(25-36), and/or any of the above mutants PYY(4-36), for example, [Lys²⁵]PPY(3-36) (amino acid Sequence=IKPEAPGEDASEELNRYYASLKHYLNLVTRQRY (SEQ ID NO:212)) is formed by combining the utazi of SEQ ID NO:36 to SEQ ID NO:1.

Also considered PYY agonists (NPY analogues), having the formula: X-Q-R₁₉-R₂₀-R₂₁-R₂₂-R₂₃-Leu-R₂₅-R₂₆-R₂₇-R₂₈-R₂₉-R₃₀-R₃₁-R₃₂-Arg-R₃₄-Arg-R36-Y, where X represented by N, or^aMe or N^aMe or desamino or acyl group containing 7 or less carbon atoms; Q is represented by R₁₇-R₁₈, R₁₈or Q; R₁₇presents Met, Arg, Nle, Nva, Leu, Ala or D-Ala; R₁₈presents Ala, Ser, Ile, D-Ala, D-Ser or D-Ile; R₁₉presents Arg, Lys or Gln; R₂₀presents Tight or Phe; R₂₁presents a Tight, Glu, His, or Ala; R₂₂presents Ser, Ala, Thr, Asn or Asp; R₂₃presents Ala, Asp, Glu, Gln Asn or Ser; R₂₅presents Arg or Gln; R₂₆presents His, Arg or Gln; R₂₇presents Phe or Taut; R₂₈presents Ile, Leu, Val or Arg; R₂₉presents Asn or Ile; R₃₀presents Leu, Met, Thr or Val; R₃₁presents Ile, Val or Leu; R₃₂presents Thr or Phe; R₃₄presents Gln, Pro, or His; R₃₆presents Phe or Taut and Y presents NH₂or HE; provided that when Q is represented by R₁₈then at least one of R₂₇and R₃₆presents Phe. Analogs of NPY have the following application: as strong agents of postsynaptic action for the treatment of hypertension and cardiogenic shock, as well as for the treatment of acute heart condition what about the cardiovascular circulatory failure and increased intracellular calcium. Cm. U.S. patent No. 5026685.

Some preferred analogs of NPY have the formula: X-R₁₈-Arg-Tyr-Tyr-R₂₂-R₂₃-Leu-Arg-is-Tyr-R₂₈-Asn-Leu-R₃₁-Thr-Arg-Gln-Arg-Tyr-NH₂where X represented by N, or^aMe or N^aMe or desamino or acyl group containing 7 carbon atoms or less; R₁₈presents Ala or Ser; R₂₂presents Ser or Ala; R₂₃presents Ala or Ser; R₂₇presents h or Taut; R₂₈presents Il or Leu; R₃₁presents Il or Val and R₃₆presents Phe or Tight, provided that at least one of R₂₇and R₃₆presents Phe. Cm. U.S. patent No. 5026685.

Others consider analogues of NPY have the formula:

X-R₁₇-R₁₈-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-R₂₇-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-R₃₆-NH₂in which R₁₇presents Arg or Leu and R₁₈presents Ser or Ala or Il and in which X, R₂₇and R₃₆above.

Another preferred analogs of NPY have the formula:

X-R₁₈-Arg-Tyr-Tyr-Ala-Ser-Leu-R₂₅-His-R₂₇-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-R₃₆-NH₂in which X is represented by dezaminiruet or^aMe or N^aMe and where R₁₈, R₂₅, R₂₇and R₃₆above.

Examples of data NPY agonists include:

pNPY(17-36)having the formula:

H-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln - Arg-Tyr-NH₂(SEQ ID NO:217)

Pepti the hNPY(17-36), having the formula:

H-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:218)

The peptide [Phe²⁷]-NPY(18-36)having the formula:

H-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:219)

The peptide [Ac-D-Ala¹⁷]-NPY(17-36)having the formula:

Ac-D-Ala-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:220)

Peptide NPY(19-36), having the formula:

H-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:221)

The peptide [Nle¹⁷]-NPY(17-36)having the formula:

H-Nle-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:222)

The peptide [D-Ser¹⁸]-NPY(18-36)having the formula:

H-D-Ser-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:223)

The peptide [Ala¹⁷,His²¹]-NPY(17-36)having the formula:

H-Ala-Ala-Arg-Tyr-His-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:224)

The peptide [D-Ile₁₈]-NPY(18-36)having the formula:

D-Ile-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:225)

The peptide [Ac-Arg¹⁷]-NPY(17-36)having the formula:

Ac-Arg-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:226)

The peptide [Gln¹⁹]-NPY(19-36), having the formula:

H-Gln-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:227)

The peptide [Phe²⁰]-NPY(18-36)having the formula:

H-Ala-Arg-Phe-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:228)

The peptide [(C^aMeLeu¹⁷]-pNPY(17-36)), having the formula:

H-C^aMeLeu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-eu-Ile-Thr-Arg-Gln-Arg-Tyr-NH ₂(SEQ ID NO:229)

The peptide [N^aMeLeu¹⁷]-pNPY(17-36)having the formula:

H-N^aMeLeu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:230)

The peptide [desamino la¹⁸]-NpY(18-36)having the formula:

desamino-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:231)

The peptide [For-Ala¹⁸Glu²³,Arg²⁶]-NPY(18-36)having the formula:

For-Ala-Arg-Tyr-Tyr-Ser-Glu-Leu-Arg-Arg-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:232)

The peptide [Nva¹⁸Ala²¹,Leu²⁸]-NPY(17-36)having the formula:

H-Nva-Ala-Arg-Tyr-Ala-Ser-Ala-Leu-Arg-His-Tyr-Leu-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:233)

The peptide [Thr²²,Gln²³]-NPY(18-36)), having the formula:

H-Ala-Arg-Tyr-Tyr-Thr-Gln-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:234)

The peptide [desamino Leu¹⁷,Asn²³,Val³⁰]-NPY(17-36)), having the formula:

N-desamino Leu-Ala-Arg-Tyr-Tyr-Ser-Asn-Leu-Arg-His-Tyr-Ile-Asn-VAL-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:235)

The peptide [Asp²²Ser²³,Thr³⁰]-NPY(18-36)having the formula:

H-Ala-Arg-Tyr-Tyr-Asp-Ser-Leu-Arg-His-Tyr-Ile-Asn-Thr-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:236)

The peptide [Gln²⁵,Leu³¹Pro³⁴]-NPY(18-36)), having the formula:

H-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Gln-His-Tyr-Ile-Asn-Leu-Leu-Thr-Arg-Pro-Arg-Tyr-NH₂(SEQ ID NO:237)

The peptide [Gln²⁵,Phe³⁶]-NPY(17-36)having the formula:

H-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-Gln-Tyr-Arg-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Phe-NH₂(SEQ ID NO:238)

The peptide [Phe³⁶]-pPYY(19-36), having the formula:

H-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Phe-NH₂ (SEQ ID NO:239)

Peptide pPYY(18-36)), having the formula:

H-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:240)

The peptide [Ac-Ser¹⁸,h²⁷]-RUU(18-36)having the formula:

Ac-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg - Tyr-NH₂(SEQ ID NO:241)

The peptide [Nle¹⁷,Asn²²,Phe²⁷]-NPY(17-36)having the formula:

H-Nle-Ala-Arg-Tyr-Tyr-Asn-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:242)

The peptide [D-Ala¹⁸Glu²¹,His³⁴]-NPY(18-36)), having the formula:

H-D-Ala-Arg-Tyr-GLU-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-His-Arg-Tyr-NH₂(SEQ ID NO:243)

The peptide [Bz-Leu¹⁷Pro³⁴,Phe³⁶]-pNPY(17-36)), having the formula:

Bz-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Pro-Arg-Phe-NH₂(SEQ ID NO:244)

The peptide [Lys¹⁹,Phe²⁷,Val²⁸]-NPY(18-36)), having the formula:

H-Ala-Lys-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Val-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:245)

The peptide [D-Ala,Val²⁸,Phe³²]-NPY(17-36)), having the formula:

D-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Val-Asn-Leu-Ile-Phe-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:246)

The peptide [^aMeSer¹⁸,Met³⁰,Phe³⁶]-NPY(18-36)), having the formula:

H-C^aMeSer-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Met-Ile-Thr-Arg-Gln-Arg-Phe-NH₂(SEQ ID NO:247)

The peptide [Arg¹⁷,Ile¹⁸,Phe^27,36]-NPY(17-36)having the formula:

H-Arg-Ile-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Phe-NH₂(SEQ ID NO:248)

The peptide [Ser¹⁸,Phe²⁷]-pNPY(17-36)having the formula:

H-Leu-Ser-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln - Arg-Tyr-NH₂(SEQ ID NO:249)

PEP is ID [N ^aMelle¹⁸,Gln²⁵,Phe²⁷]-NPY(18-36)having the formula:

N^aMelle-Arg-Tyr-Tyr-Ser-Ala-Leu-Gln-His-Phe-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:250)

The peptide [D-Ser¹⁸,Phe³⁶]-NPY(18-36)having the formula:

H-D-Ser-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Phe-NH₂(SEQ ID NO:251)

The peptide [Asp²³,Arg²⁶]hNPY(17-36)having the formula:

H-Met-Ala-Arg-Tyr-Tyr-Ser-Asp-Leu-Arg-Arg-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:252)

The peptide [Glu²³,Ile²⁹]-NPY(18-36)having the formula:

H-Ala-Arg-Tyr-Tyr-Ser-Glu-Leu-Arg-His-Tyr-Ile-Ile-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:253)

The peptide [D-Ala¹⁷]-NPY(17-36)-OH having the formula:

D-Ala-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-OH (SEQ ID NO:254).

Other agonists, peptide YY have the formula:

in which:

X - chain of 0-5 amino acids, including a circuit in which N-terminal amino acid is linked to R₁and R₂

Y is a chain of 0-4 amino acids, including a circuit in which C-terminal amino acid is linked to R₃and R₄,

R₁- H₁-C₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

R₂- H₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthyl is ethyl), With₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

And²²- aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or deleted;

And²³- Ser, Thr, Ala, N-Me-Ser, N-Me-Thr, N-Me-Ala or deleted;

A²⁴Is Leu, Ile, Vat, Trp, Gly, Aib, Anb, N-Me-Leu or deletion;

A²⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H₁-C₁₀is an alkyl group branched or straight-chain or aryl group), Orn, or deletion;

And²⁶Is His, Thr, 3-Me-His, 1-Me-His, β-pyrazolines, N-Me-His, Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H₁-C₁₀is an alkyl group branched or straight-chain or aryl group), Orn, or deletion;

And²⁷- aromatic amino acid other than Tight;

And²⁸Is Leu, Ile, Vat, Trp, Aib, Aib, Anb, or N-Me-Leu;

And²⁹Is Asn, Ala, Gln, Gly, Trp, or N-Me-Asn;

A³⁰Is Leu, Ile, Val, Trp, Aib, Anb, or N-Me-Leu;

A³¹- Vat, He, Trp, Aib, Anb, or N-Me-Val;

A³²- Thr, Ser, N-Me-Set, or N-Me-Thr;

R₃- H₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

R₄- H, C₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (for example, phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were) or its pharmaceutically acceptable salt. Cm. U.S. patent No. 5574010.

Especially preferred agonists of this formula, suitable for use in the method corresponding to the description of the invention, include:

N-α-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO:255).

Other agonists, peptide YY have the formula:

in which:

N-terminal amino acid is linked to R₁and R₂;

Y is a chain of 0-4 amino acids, including chain, C-terminal amino acid which is linked to R₃and R₄;

R₁- H, C₁-C₁₂-alkyl, C₆-C₁₈-aryl, C₁-C₁₂-acyl, C₇-C₁₈-aralkyl or₇-C₁₈-alkaryl;

R₂- H, C₁-C₁₂-alkyl, C₆-C₁₈-aryl, C₁-C₁₂-acyl, C₇-C₁₈-aralkyl or₇-C₁₈-alkaryl;

And²⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or straight-chain or aryl group), Orn, or deletion;

And²⁶- Ala, His, Thr, 3-Me-His, 1-Me-His, β-perosonally, N-Me-His, Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H₁-C₁₀is an alkyl group is as branched or straight-chain or aryl group), Orn or deletion;

And²⁷- aromatic amino acid;

And²⁸Is Leu, Ile, Val, Trp, Aib, Anb, or N-Me-Leu;

And²⁹Is Asn, Ala, Gln, Gly, Trp, or N-Me-Asn;

A³⁰Is Leu, Ile, Val, Trp, Aib, Anb, or N-Me-Leu;

A³¹- Val, Ile, Trp, Aib, Anb, or N-Me-Val;

A³²- Thr, Set, N-Me-Set or N-Me-Thr or D-Trp;

R₃- H₁-C₁₂-alkyl, C₆-C₁₈-aryl, C₁-C₁₂-acyl With₇-C₁₈-aralkyl or₇-C₁₈-alkaryl and

R₄- H₁-C₁₂-alkyl, C₆-C₈-aryl, C₁-C₁₂-acyl With₇-C₁₈-alkaryl or₇-C₁₈-alkaryl or its pharmaceutically acceptable salt. Note that unless stated otherwise, all operations described in this context agonist peptide YY each amino acid residue such as Leu and A1 represents the structure NH--C(R)H-CO--, where R is a side chain. The line between amino acid residues are peptide bonds that link amino acids. In addition, if the remainder of the amino acid is optically active, it is present in the configuration of the L-shape that is implied, if not expressly stated, the D-form.

Other PYY agonists have the formula:

in which:

X - chain of 0-5 amino acids, including a circuit in which N-terminal amino acid is linked to R₁and R₂;

Y is a chain of 0-4 amino acids, including a circuit in which the end of the second amino acid is linked to R ₃and R₄;

R₁- H, C₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

R₂- H, C₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

And²²- aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or deleted;

And²³- Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N-Me-Ala or deleted;

A²⁴Is Leu, Ile, Val, Trp, Gly, Nle, Nva, Aib, Anb, N-Me-Leu or deletion;

A²⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lye-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or aryl group), Orn, or deletion;

And²⁶- Ala, His, Thr, 3-Me-His, 1-Me-His, β-piratically, N-Me-His, Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or aryl group), Orn, or deletion;

And²⁷- aromatic amino acid other than Tight;

And²⁸Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;

A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;

A³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;

A³¹- Val, Leu, Ile, Trp, Nle, Nva, Aib, Anb, or N-Me-Val;

A³²- Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;

R₃- H₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were) and

R4 is H₁-C₁₂alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were) or its pharmaceutically acceptable salt.

In preferred embodiments, implementation And²⁷- Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi or Dip.

In preferred embodiments, the implementation of X-And¹⁷-And¹⁸-And¹⁹-And²⁰-And²¹where

And¹⁷- Cys, Leu, Ile, Val, Nle, Nva, Aib, Anb, or N-Me-Leu;

And¹⁸Is Cys, Ser, Thr, N-Me-Ser or N-Me-Thr;

And¹⁹Is Arg, Lys, Homo-AGD, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H₁-C₁₀is an alkyl group branched or non-branched chain or C₆-C₁₈-aryl group), Cys, or Orn;

And²⁰- aromatic amino acid or Cys and

And²¹- aromatic amino acid, Cys or its pharmaceutically acceptable salt. In another preference is sustained fashion options exercise Y-A ³³-A³⁴-A³⁵-A³⁶where

And³³Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or C₆-C₁₈-aryl group), Cys, or Orn;

And³⁴- Cys, Gln Asn, Ala, Gly, N-Me-C1n, Aib or Anb;

A³⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or₆-C₁₈-aryl group), Cys, or Orn and

And³⁶- aromatic amino acid, Cys or its pharmaceutically acceptable salt. Cm. U.S. patent No. 5604203.

Concrete option implementation includes compounds having the formula:

N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ. ID. NO:325),

H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ. ID. NO:326), N-α-Ac-Ala-Ser-Leu-Arg-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ. ID. NO:327), N-α-Ac-Ala-Ser-Leu-Arg-His-THI-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ. ID. NO:328),

N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ. ID. NO:329), or their pharmaceutically acceptable salt.

Other PYY agonists have the formula:

in which N-terminal amino acid is linked to R₁and R₂; Y is a chain of 0-4 amino acids, including a circuit in which C-terminal amino acid is linked to R₃and R₄;

R₁- H, C₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, nafti is acetyl), With₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

R₂- H, C₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were);

And²⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or₆-C₁₈-aryl group), Orn, or deletion;

A²⁶-Ala, His, Thr, 3-Me-His, 1-Me-His, β-perosonally, N-Me-His, Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or₆-C₁₈-aryl group), Orn, or deletion;

And²⁷- aromatic amino acid;

And²⁸Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;

And²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;

And³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;

A³¹- Val, Ile, Trp, Nle, Nva, Aib, Anb, or N-Me-Val;

A³²- Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;

R₃- H₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-the ₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were) and

R₄- H₁-C₁₂-alkyl (e.g. methyl), C₆-C₁₈aryl (e.g. phenyl, naphthylacetyl)₁-C₁₂-acyl (e.g. formyl, acetyl and myristoyl)₇-C₁₈-aralkyl (e.g., benzyl) or (C₇-C₁₈-alkaryl (for example, p-were) or its pharmaceutically acceptable salt. Cm. U.S. patent No. 5604203.

In specific embodiments, implementation And²⁷- Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Dip.

In specific embodiments, the implementation of X-And³³-And³⁴-And³⁵-And³⁶where

And³³Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, [Lys-∈-NH-R] (where R is H₁-C₁₀is an alkyl group branched or non-branched chain or₆-C₁₈-aryl group), Cys, or Orn;

And³⁴Is Gln, Asn, Ala, Gly, N-Me-Gln, Aib, Cys or Anb;

A³⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R (where R is H, C₁-C₁₀is an alkyl group branched or non-branched chain or₆-C₁₈-aryl group), Cys, or Orn and

And³⁶- aromatic amino acid, Cys or its pharmaceutically acceptable salt.

Preferably, when the compound has the formula:

N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ. ID. NO:324).

Examples of PYY agonists include:

Other PYY agonists include neutrophil receptor YY2-specific peptides having the formula:

X1(-x2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-x14)_n-H, where X1 is NH, CH₃WITH or one or two natural amino acids.

X2 is Leu, Ile or Val.

X3 is Arg, Lys or His.

X4 - His, Lys or Arg.

X5 - Tight or Phe.

X6 is Leu, Ile or Val.

X7 is Asn or Gln.

X8 is Leu, Ile or Val.

X9 is Leu, Ile or Val.

X10 is Thr or Ser.

X11 is Arg, His or Lys.

X12 - Gln or Asn.

X13 is Arg, His or Lys.

X14 - Tight or Phe.

X15 - COOH, NH₂or one or two natural amino acids with the terminal amino acid in normal or carboxamide form, and n=1-5. Cm. U.S. patent No. 5696093.

Examples of agonists include:

CH₃CO-L-R-H-Y-L-N-L-L-T-R-Q-R-Y-NH₂(SEQ ID NO:298)

CH₃CO-L-R-H-Y-I-N-L-I-T-R-Q-R-Y-NH₂(SEQ ID NO:299)

NH₂-L-R-H-Y-L-N-L-L-T-R-Q-R-Y-NH₂(SEQ ID NO:300)

NH₂-L-R-H-Y-I-N-L-I-T-R-Q-R-Y-NH₂(SEQ ID NO: [301)

Other agonists PY have the formula:

N-α-R₁-[Nle^24,28,30,Trp²⁷,Nva³¹,ψ^35/36]PYY(22-36)-NH₂,

N-α-R₁-[Nle^24,28,Trp^27,30,Nva³¹,ψ^35/36]PYY(22-36)-NH₂,

N-α-R₁-[Nle^24,28,30,Phe²⁷,Nva³¹,ψ^35/36]PYY(22-36)-NH₂,

N-α-R₁-[Nle^24,28,Phe²⁷,Trp³⁰,Nva³¹,ψ^35/36]PYY(22-36)-NH₂,

N-α-R₁-[Trp³⁰,ψ^35/36]PYY(25-36)-NH₂,

N-α-R₁-[Trp³⁰]PYY(25-36)-NH₂,

N-α-R₁-[Nle^24,28,Trp³⁰,Nva³¹,ψ^35/36]PYY(22-36)-NH₂and

N-α-R₁-[Nle²⁸,Trp³⁰,Nva³¹,ψ^35/36]PYY(22-36)-NH₂or their pharmaceutically acceptable salt,

where R₁- N, (C_1-12)-alkyl or (C_1-12)-acyl and

ψ - pseudopeptide connection selected from the group consisting of-CH₂-NH--, --CH₂-S--, --CH₂-CH₂--, --CH₂--O-- and --CH₂--CO--. Cm. U.S. patent No. 6046162.

In particular the compounds of the group of compounds described in the preceding paragraph, R₁- acetyl and ψ is --CH₂-NH--.

A selected group of compounds selected from the group consisting of

N-α-Ac-[Nle^24,28,30,Trp²⁷,Nva³¹,ψ^35/36]PYY(22-36)-NH₂, (SEQ ID NO:302)

N-α-Ac-[Nle^24,28,Trp^27,30,Nva³¹,ψ^35/36]PYY(22-36)-NH₂, (SEQ ID NO:303)

N-α-Ac-[Nle^24,28,30,Phe²⁷,Nva³¹,ψ^35/36]PYY(22-36)-NH², (SEQ ID NO:304)

N-α-Ac-[Nle^24,28,Phe²⁷,Trp³⁰,Nva 31,ψ^35/36]PYY(22-36)-NH₂, (SEQ ID NO:305)

N-α-Ac-[Trp³⁰,ψ^35/36]PYY(25-36)-NH₂, (SEQ ID NO:306)]

N-α-Ac-[Trp³⁰]PYY(25-36)-NH₂(SEQ ID NO:307), and

N-α-Ac-[Nle²⁸,Trp³⁰,Nva³¹,ψ^35/36]PYY(22-36)-NH₂, (SEQ ID NO:308), or their pharmaceutically acceptable salts.

Another specific compound has the formula N-α-Ac-[Nle^24,28,Trp³⁰, Nva.sup.³¹,ψ^35/36]PYY(22-36)-NH₂(SEQ. ID. NO:309) or its pharmaceutically acceptable salt.

Other PYY agonist has the formula (A),

containing one or two pseudopeptide communication, where each pseudopeptide communication independently selected from the group consisting of-CH₂-NH--, --CH₂-S--, --CH₂--CH₂--, --CH₂-O-and-CH₂-CO--, where:

R₁₀- a chain of 0-5 amino acids, including a circuit in which N-terminal amino acid is linked to R₁and R₂through side-chain N-terminal amino acids or nitrogen of the amino group of the N-terminal amino acids;

R₂₀- a chain of 0-4 amino acids, including a circuit in which C-terminal amino acid is linked to R₃and R₄through side-chain C-terminal amino acids or carbon atom of the carboxylic group of the C-terminal amino acids;

Each of R₁, R₂, R₃and R₄independently selected from the group consisting of H, (C₁-C₁₂)-alkyl, (C₆-C₁₈)-aryl,(C ₁-C₁₂)-acyl, phenyl(C₁-C₁₂)-alkyl and ((C₁-C₁₂)alkyl)_1-5is phenyl;

And²²- aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or deleted;

And²³- Ser, Thr, Ala, N-Me-Ser, N-Me-Thr, N-Me-Ala or deleted;

A²⁴Is Leu, Ile, Nle, Val, Trp, Gly, Aib, Anb, N-Me-Leu or deletion;

A²⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-p.∈-NH-Z, Orn or is deleted;

A²⁶Is His, Thr, 3-Me-His, 1-ME-His, β-pyrazolidinone, N-Me-His, Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-Z, Orn or is deleted; And²⁸Is Leu, Ile, Nle, Val, Trp, Aib, Anb, or N-Me-Leu;

A²⁹Is Asn, Ala, Gln Gly, Trp or N-Me-Asn;

A³⁰Is Leu, Ile, Nle, Fla, Val, Trp, Aib, Anb, or N-Me-Leu;

And³¹- Val, Nva, Ile, Trp, Aib, Anb, or N-Me-Val and

A³²- Thr, Ser, N-Me-Ser or N-Me-Thr,

where Z in each case independently selected from the group consisting of H, (C₁-C₁₀)-alkyl and (C₆-C₁₈)-aryl or its pharmaceutically acceptable salt. Cm. U.S. patent No. 6046167.

In a sample of specific compounds of the group of compounds described in the preceding paragraph, R₁₀- And¹⁷-And¹⁸-And¹⁹-And²⁰-And²¹,

where a¹⁷- Cys, Leu, Ile, Val, Nle, Nva, Aib, Anb, or N-Me-Leu;

A¹⁸Is Cys, Ser, Thr, N-Me-Ser or N-Me-Thr;

A¹⁹Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-Rg, Cys or Orn;

A²⁰- aromatic amino acid or Cys;

A²¹- aromatic amino acid or Cys;

R₂₀- A³³-A³⁴-A³⁵-A³⁶,

A³³Is Arg, Lys, Homo-Ar, diethyl-Homo-Arg, Lys-∈-NH-R₅, Cys or Orn;

A³⁴- Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb;

A³⁵Is Arg, Lys, Homo-Arg, diethyl-Homo-Arg, Lys-∈-NH-R₅, Cys or Orn and

A³⁶- aromatic amino acid or Cys,

where R₅for each case independently selected from the group consisting of H₁, (C₁-C₁₀)-alkyl and (C₆-C₁₈)-aryl.

Sample of specific compounds of the preceding group is represented by the compounds of the formula N-α-Ac-[Fla²⁷]PYY(25-36)-NH₂and N-α-Ac-[Fla²⁷]PYY(22-36)-NH₂or its pharmaceutically acceptable salt.

Another group of PYY agonist has the formula:

or its pharmaceutically acceptable salt, in which

------ represents an optional bond between amino acids, which shows the existence of a relationship with each other, where each link is independently selected from the group consisting of --S--S--, only when associated amino acids are represented as Cys-Cys, -CO-NH-, -CH₂-NH - and

provided that when the optional bond represented

it replaces two amino acids, which are attached to an optional bond; q=1-4; m=1-4;

R₃₀- HE or-O-R₁provided that when A¹-And⁷removed, R₃₀can also be NH-R₁where R₃₀joined at the mu carbon carboxyl C-terminal amino acids;

each of R₁and R₂for each case independently selected from the group consisting of H, (C₁-C₁₂)-alkyl, (C₆-C₁₈)-aryl, (C₁-C₁₂)-acyl, phenyl-(C₁-C₁₂)-alkyl and ((C₁-C₁₂)-alkyl)_1-5-phenyl, where R₁and R₂attached to the amine nitrogen of the N-terminal amino acids;

And¹removed or presents D - or L-forms of the following amino acids: Thr, Tight, Fla, Bth, Nal, Tic, Tic-OH, Dip, Bip, or optionally substituted Phe, where Phe optionally substituted by one to five substituents selected from the group consisting of (C₁-C₄)-alkyl, halogen, (C₁-C₄-alkoxygroup, amino - and nitrogroup;

And²removed or presents D - or L-forms of the following amino acids: Il, Val, Leu, Nle, Anb, Aib, Pro, Gln or Asn;

And³removed or presents D - or L-forms of the following amino acids: Asn, Gln, Glu, Asp, Orn, Lys, Dpr or Cys;

And⁴removed or presents D - or L-forms of the following amino acids: Il, Val, Leu, Nle, Anb, Aib or Pro;

And⁵removed or presents D - or L-forms of the following amino acids: Il, Val, Leu, Nle, Anb, Aib, Pro, Glu, Asp, Om, Lys, Dpr or Cys;

And⁶removed or presents D - or L-forms of the following amino acids: hr, Ser, Thr, Tight, Fla, Bth, Nal, Tic, Tic-OH, Dip, Bip, or optionally substituted Phe, where Phe optionally substituted by one to five substituents selected from the group consisting of C ₁-C₄)-alkyl, halogen, (C₁-C₄-alkoxygroup, amino - and nitrogroup;

And⁷removed or presents D - or L-forms of the following amino acids: Arg, Lys, Homo-Arg, dialkyl-Homo-Arg, Lys-∈-NH-R7 or Orn;

And⁸removed or presents D - or L-forms of the following amino acids: Nva, Val, Ile, Leu, Nle, Anb, Aib, Pro, Gln Asn, Glu, Asp, Orn, Lys, Dpr or Cys;

And⁹removed or presents D - or L-forms of the following amino acids: Arg, Lys, Homo-Arg, dialkyl-Homo-Arg, Lys-∈-NH-R7 or Orn and

And¹⁰removed or presents D - or L-forms of the following amino acids: Tight, Trp, Fla, Bth, Nal, Tic, Tic-OH, Dip, Bip, tyramine or optionally substituted Phe, where Phe optionally substituted by one to five substituents selected from the group consisting of (C₁-C₄)-alkyl, halogen, (C₁-C₄-alkoxygroup, amino and nitro, or the appropriate decarboxylating optionally substituted Phe;

where R₇for each case independently selected from the group consisting of H₁(C₁-C₁₀)-alkyl and (C₆-C₁₈)-aryl, provided that not all And¹-And¹⁰remove at the same time. Cm. U.S. patent No. 6046167.

Sample of specific compounds of the group of compounds represented in the immediately preceding paragraph contains

or their pharmaceutically reception which controls salt.

PYY and PYY agonists can be modified by well known methods, such as amidation, glycosylation, acylation (e.g., acetylation, sulfation, phosphorylation, cyclization, lipidization, tahilramani. How lipidization derivatives of fatty acids sulfgidrilnami compounds disclosed in U.S. Patent No. 5936092, U.S. Patent No. 6093692 and U.S. Patent No. 6225445. Derivatives of fatty acids sulfgidrilnami PYY and PYY agonists containing conjugated with fatty acids products by a disulfide bond, is used for the delivery of PYY and PYY agonists in nerve cells and tissues. This modification significantly increases the absorption of compounds relative to the speed of absorption of unconjugated compounds, as well as prolong the retention of compounds in the blood and tissues. Moreover, the disulfide linkage in the conjugate is very labile in the cells and, thus, facilitates the intracellular release of the intact compounds from fatty acid molecules.

Fatty acids as components of phospholipids are the major part of cell membranes. Thanks to the lipid nature of the fatty acid can easily penetrate the cell membrane and interact with it without causing toxic effects. Consequently, fatty acids represent a potentially effective ligand carrier for picking up and proteins and peptides. Strategic use of fatty acids for delivery of proteins and peptides include covalent modification of proteins and peptides and the use of emulsions of fatty acids.

To obtain data conjugates sulphotransferase PYY and PYY agonist is attached to the derived fatty acids through reversible biodegrading disulfide bonds. Assume that this conjugate will bind to the apical side of the cell membrane, to achieve basolateral membrane of the gastro-intestinal epithelium resulting membrane transport and included in the cycle with access to interstitial fluid in the recovery disulfide bonds.

Data lepidosirenidae connection PYY and PYY agonist have the General formula

where R is a residue selected from the PYY or PYY agonist; R₁is hydrogen, lower alkyl or aryl; R₂- oil containing structure and R₃- --HE oil containing structure or a chain of amino acids containing 1 or 2 amino acids and ending WITH₂H or-COR₂. Cm. U.S. patent No. 5936092. These conjugates are particularly effective in enhancing the absorption and prolonged retention PYY and PYY agonists in the blood and tissues.

Typical alkyl groups include₁-C₆is an alkyl group, including methyl, ethyl, propyl, isoprop is l, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl etc.

Preferred aryl groups include₆-C₁₄-aryl groups, and typically include phenyl, naftalina, fluoroanilino, phenanthroline and anthracyline group.

The term "oil containing structure (molecule)" refers either to the lipid group as such, or to the group of hydrocarbon-based (in particular, one or more amino acids)containing the lipid group. The term "lipid group" refers to a hydrophobic Deputy containing 4-26 carbon atoms, preferably 5 to 19 carbon atoms. Suitable lipid groups include, but are not limited to, the following: palmitic (C₁₅H₃₁), oleyl (C₁₅H₂₉), stearyl (C₁₇H₃₅), Holt and dezoksiholatom.

In PCT application No. WO 00/34236 describe conjugates of a drug and the carrier and strategy synthesis, aimed at obtaining them, as well as methods of synthesis, intermediate products and final products used for the introduction and release of biologically active compounds containing amino groups. Data lepidosirenidae connection PYY and PYY agonists have a General formula I

where R₂selected the C group, consisting of hydrogen, halogen, alkyl, or aryl, where the alkyl or aryl group optionally substituted by one or more alkoxygroup, alkoxyalkyl, alkanoyl, nitrogroup, cycloalkyl, alkenyl, quinil, alkanoyloxy, alkyl or halogen atoms;

R₃- lipophilic group; one of R₄and R₅and PYY or PYY agonist and others

R₄and R₅- OR₆where R₆is hydrogen, alkali metal, or a negative charge;

X is oxygen or sulfur;

Y - bridge natural or unnatural amino acid; n is zero or 1, and

m is an integer from 0 to 10.

Typical alkyl groups include₁-C₆is an alkyl group, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl etc.

Typical alkoxygroup include colorazione any of the above alkyl groups.

Typical alkoxyalkyl groups include any of the above alkyl groups substituted by alkoxygroup, such as methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, intoximeter, exactimate, methoxyethyl, methoxypropyl, methoxybutyl, methoxyphenyl, methoxyacetyl etc.

Preferred aryl groups include₆-sub> 14-aryl groups, and typically include phenyl, naftalina, fluoroanilino, phenanthroline and anthracyline group.

Typical alkoxy-substituted aryl groups include the above-mentioned aryl group, substituted by one or more of the above alkoxygroup, for example, 3-methoxyphenyl, 2 - ethoxyphenyl etc.

Typical alkyl substituted aryl groups include any of the above aryl groups substituted With any of the₁-C₆is an alkyl group, including group Ph(CH₂)_nwhere n=1-6, for example toluene, o-, m - and p-xylyl, ethylphenyl, 1-propylphenyl, 2-propylphenyl, 1-butylphenyl, 2-butylphenyl, tert-butylphenyl, 1-pentylphenol, 2 - pentylphenol, 3-pentylphenol.

Typical alkeneamine groups include₂-C₆-alkeline group, for example etinilnoy, 2-propenyloxy, Isopropenyl, 2-butenyloxy, 3-butenyloxy, 4-pentanediol, 3-pentanediol, 2-pentanediol, 5-hexenyl, 4-hexenyl, 3-hexanediol and 2-hexenyl group.

Typical alkyline groups include₂-C₆-alkyline group, for example etinilnoy, 2-propenyloxy, 2-butenyloxy, 3-butenyloxy, 4-Punchinello, 3-Punchinello, 2-Punchinello, 5-hexanediol, 4-hexanediol, 3-hexanediol and 2-hexylamino group.

Typical alkenyl or alkenylamine aryl groups include any of the above With 6-C₁₄-aryl groups, substituted by any of the above With₂-C₆-alkenyl or₂-C₆-etkinlik groups, for example ethynylphenyl, 1-propylphenyl, 2-propylphenyl, 1-butylphenyl, 2-butylphenyl, 1-pentylphenol, 2-pentylphenol, 3-pentylphenol, 1-heckenlively, 2-heckenlively, 3-heckenlively, ethynylphenyl, 1-propylphenyl, 2-propylphenyl, 1-butylphenyl, 2-butylphenyl, 1-pentylphenol, 2-pentylphenol, 3-pentylphenol, 1-hexylphenyl, 2-hexylphenyl, 3-hexylphenyl group.

Typical halogen groups include fluorine, chlorine, bromine and iodine.

Typical halogen-substituted alkyl groups include C₁-C₆is an alkyl group substituted by one or more atoms of fluorine, chlorine, bromine and iodine, for example permetrina, deformational, triptoreline, panafcortelone, 1,1-deperately and trichlorethylene group.

Typical alcoholnye groups include_1-5C(=O)-alcoholnye group, for example acetyl, propionyl, butanoyloxy, pentanoyl and hexanoyl group, or arylalkylamine group, for example With_1-5C(=O)-alkanoyloxy group, substituted by any of the above aryl groups.

Typical cycloalkyl groups include_3-8cycloalkyl the group, including cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptyl and cyclooctyl group.

The term "lipophilic group", as used in this context, refers to either natural lipid as such, hydrophobic branched or unbranched hydrocarbon containing from about 4 to about 26 carbon atoms, preferably from about 5 to about 19 carbon atoms, fatty acid or its ether complex, or a surfactant. Suitable lipophilic groups include, but are not limited to, alcoholnye group with a long chain, including: Palmitoyl (C₁₅H₃₁), oleoyl (C₁₅H₂₉), stearyl (C₁₇H₃₅), lauryl (C₁₁H₂₃), was Halil and myristoyl C₁₃H₂₇).

The term "natural or unnatural amino acid," as used in this context, refers to any of the 21 natural amino acids, and D-forms of amino acids, blocked L - and D-forms of amino acids, such as amino acids, blocked by amidation or acylation, substituted amino acids (e.g. amino acids, substituted alkyl groups or cycloalkyl groups such as cyclopropyl or cyclobutyl, creating a physical barrier), in which the substitution introduces the amino acid is the conformational restriction. Preferred natural amino acids used in this invention, such as amino acids or components of a peptide or protein represented by alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, γ-glutamic acid, glutamine, glycine, histidine, isoleucine, norleucine, leucine, lysine, methionine, ornithine, phenylalanine, Proline, hydroxiproline, serine, threonine, tryptophan, tyrosine, valine, γ-carboxyglutamic or O-phosphoserine. Preferred non-natural amino acids used in this invention, such as amino acids or components of a peptide or protein represented by any one of β-amino acids, for example, α-alanine, γ-aminobutyric acid, γ-(AMINOPHENYL)-butyric acid, α-aminoadamantane acid, ∈-aminocaproic acid, 7-aminoheptanoic acid, aminobenzoic acid, aminophenylacetic acid, aminopenicillanic acid, cysteine (ACM), methanesulfonate, phenylglycinol, Norvaline, ornithine Delta-ornithine, p-nitro-phenylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and thioproline.

This invention is also directed towards methods of obtaining lepidosiren conjugates PYY and PYY agonists, pharmaceutical compositions containing lepidosirenidae conjugates PYY and PYY agonists, and ways increases the level of delivery contains the amino group of PYY and PYY agonists in the cell.

In this description of the invention presents also chemically modified derivatives of PYY and PYY agonists, which may provide additional advantages such as increased solubility, stability and circulation time of the polypeptide, or decreased immunogenicity (see U.S. Patent No. 4179337). Data modified derivatives include PYY and PYY agonists, modified philibosian. The term "pegylated" and "tahilramani" refers to the process reaction polyalkyleneglycol, preferably activated polyalkyleneglycol with an agent that facilitates the action, such as an amino acid, for example lysine, with the formation of covalent bonds. Although tahilramani" is often carried out using polyethylene glycol or its derivatives, such as methoxypolyethyleneglycol, the limitation of the term of this agent is not provided, and it is intended to include any other effective polyalkyleneglycol, such as polypropyleneglycol.

Chemical structure for derivatization may be selected from water-soluble polymers, such as polyethylene glycol, copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol and the like Polypeptides may be modified at random positions of the molecule or specific provisions of the mole the uly and can include one, two, three or more attached chemical molecules.

The polymer may have any molecular weight and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 KD and about 100 KD (the term "about" indicates that in preparations of polyethylene glycol, some molecules will have a lot more or a bit less, than the stated molecular weight) for ease of handling and fabrication. You can use other values depending on the desired therapeutic profile (e.g., the desired duration of the delayed output effects, if any on biological activity, the ease of handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of approximately 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000, 10500, 11000, 11500, 12000, 12500, 13000, 13500, 14000, 14500, 15000, 15500, 16000, 16500, 17000, 17500, 18000, 18500, 19000, 19500, 20000, 25000, 30000, 35000, 40000, 50000, 55000, 60000, 65000, 70000, 75000, 80000, 85000, 90000, 95000 or 100000 CD.

As mentioned above, the polyethylene glycol may have a branched structure. Extensive politetilenglikol described, for example, in U.S. Patent No. 5643575; articles Morpurgo and the W., Appl. Biochem. Biotechnol., 56:59-72, (1996); Vorobjev et al., Nucleosides Nucleotides, 18:2745-2750, (1999) and Caliceti et al., Bioconjug. Chem., 10:638-646, (1999).

Molecules of polyethylene glycol (or other chemical structure) should be attached to the polypeptide and protein consideration of the effects of functional and antigenic domains of the polypeptides or proteins. There are several ways of joining, available to competent specialists in this field, for example, see patent application EP 0401384 (linking PEG to G-CSF), see also Malik et al., Exp. Hematol., 20:1028-1035, (1992) (described tahilramani GM-CSF using treilhard). For example, the polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. The reaction groups represented by the groups with which may be associated with an activated molecule of polyethylene glycol. Amino acid residues having a free amino group may include lysine residues and N-terminal amino acid residues; residues having a free carboxyl group may include aspartic acid residues, glutamic acid residues and C-terminal residues of amino acids. Sulfhydryl groups can also be used as reactive groups for attaching molecules of polyethylene glycol. Preferred for therapeutic purposes t is aetsa joining the amino group, such as joining the N-end, or a group of lysine.

As suggested above, the polyethylene glycol may be attached to proteins and polypeptides through communication with any of a number of amino acid residues. For example, the polyethylene glycol may be associated with proteins and polypeptides by covalent bonds with residues of lysine, histidine, aspartic acid, glutamic acid or cysteine. You can use one or more methods, reactions to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid or cysteine) polypeptide or protein or amino acid residues of more than one type (for example, lysine, histidine, aspartic acid, glutamic acid or cysteine, or combinations of these) protein or polypeptide.

May be required proteins and polypeptides chemically modified at the N end. For example, polyethylene glycol may be made choice among the many molecules of polyethylene glycol (molecular weight, branching and so on), the ratio of molecules of polyethylene glycol and molecules of the protein (or peptide) in the reaction mixture, the type of reaction tahilramani and the method of obtaining the selected protein pegylated at the N end. The method of producing drug, pegylated at the N-end is (i.e. branch if necessary, a given molecule from other monopegylated molecules), may provide cleaning material, pegylated at the N end, from a population of pegylated protein molecules. Selective proteins, chemically modified by modification of N-end may be obtained by the alkylation, in which use differences in reactivity of different types of primary amino groups (lysine relative to N-terminal)available for derivatization in a particular protein. In the respective reaction conditions is achieved practically selective derivatization of the protein at the N end of the polymer containing a carbonyl group.

As stated above, pegylation of proteins and polypeptides can be carried out in any number of ways. For example, the polyethylene glycol may be attached to a protein or polypeptide, either directly or using an intermediate linker. Bestinternet system for attaching polyethylene glycol to proteins and polypeptides are described in articles Delgado et al., Crit. Rev. Thera. Drug Carrier Sys., 9:249-304, (1992), Francis et al., Intern. J of Hematol., 68:1-18, (1998); U.S. Patent No. 4002531, U.S. Patent No. 5349052, patent applications WO 95/06058 and WO 98/32466.

In one of the systems of attaching polyethylene glycol directly to amino acid residues of proteins and polypeptides without intermediate linker use t etilirovany MPEG, which is obtained by modifying monometoksipolietilenglikolya (MPEG) using treilhard (ClSO₂CH₂CF₃). The reaction of the protein or polypeptide with trailrunner MPEG polyethylene glycol directly attached to the amine groups of the protein or polypeptide. Thus, the invention includes conjugates of protein and polyethylene glycol formed during the reaction of proteins and polypeptides with one molecule of polyethylene glycol containing 2,2,2-trifluoroethanesulfonyl group.

The polyethylene glycol may also be attached to proteins and polypeptides using a number of different intermediate linkers. For example, U.S. Patent No. 5612460 discloses urethane linkers for binding polyethylene glycol to proteins. Conjugates of protein and polyethylene glycol, in which the polyethylene glycol is attached to a protein or polypeptide by a linker can also be obtained by reaction of proteins or polypeptides with compounds, such as MPEG-succinimidylester, MPEG, activated 1,1'-carbonyldiimidazole, MPEG-2,4,5-trichlorophenylacetic, MPEG-p-nitrophenylarsonic and various derivatives of MPEG-succinate. A number of additional derivatives of polyethylene glycol and chemical methods the reactions of addition of polyethylene glycol to proteins and polypeptides are described in patent application WO 98/32466.

The number of molecules of poly is etilenglikola, attached to each protein or polypeptide (i.e., the degree of substitution)may also vary. For example, pegylated proteins and polypeptides can be associated on average with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20 or more molecules of polyethylene glycol. Similarly, the average degree of substitution lies at such intervals as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19 or 18-20 molecules of polyethylene glycol/molecule, protein or polypeptide. Methods for determining the substitution are discussed, for example, article Delgado et al., Crit. Rev. Thera. Drug Carrier Sys., 9:249-304, (1992). Proteins and polypeptides containing almost pantagonia the polymer, preferably the polyalkylene glycols can be obtained, for example, as described in U.S. Patent No. 5428128, U.S. Patent No. 6127355 and U.S. Patent No. 5880131.

For the implementation of the covalent binding of polyethylene glycol (PEG) with the protein or polypeptide of hydroxyl end groups of PEG must first be converted into reactive functional groups. This process is often termed "activation" and the resulting product is called "activated PEG". Often use methoxypolyethyleneglycol (MPEG) with distal cap in the form of a reactive functional group. One such activated PEG presents succinimidylester derivative of PEG (SS-PEG). Cm. article Abuchowski et al., Cancer Biochem. Biophys., 7:175-186,(1984) and U.S. Patent No. 5122614, which discloses a polyethylene glycol-N-succinimidylester its receipt.

Alternative almost pantagonia polymers that can be used in the practical implementation of this invention include materials such as dextran, polyvinylpyrrolidone, polysaccharides, starches, polyvinyl alcohols, polyacrylamides or other similar non-immunogenic polymers. Competent professionals in this field will recognize that the foregoing is merely illustrative and is not intended to restrict the types of polymeric substances suitable for use in this context.

In one aspect of this invention, the polymer is introduced into the molecule of the peptide or protein after her functionalitywith or trigger for the reaction and by joining one or more amino acids. Ordinary experts in this field under the activation realize that the polymer functionalitywith by incorporating the desired reactive group. See, for example, U.S. Patent No. 4179337 and U.S. Patent No. 5122614. In this embodiment, the hydroxyl end groups of the polyalkylene glycols turn and activate with obtaining reactive functional groups.

In another aspect of the invention the polymer before introduction into the molecule of the polypeptide or protein kongugiruut with a molecule that facilitates the reaction. The molecule about archusa reaction, preferably represented by amino acid such as lysine, but are also considered molecules, which are not amino acids. In this aspect includes multifunktionsebene organic molecules, such cakalele or substituted alkali. Can be obtained from these molecules, which contain a nucleophilic functional group such as amine, and an electrophilic group, such as acid, as well as appropriately functionalized site for conjugation with the desired polymer or polymers.

Molecules that facilitate the reaction, you can simplify the introduction of the polymer molecule peptide or protein in the synthesis. For example, the illustration for the above are the polyalkylene glycols, associated with facilitating the reaction of amino acids or residues of polypeptides or proteins with suitable binding agents. A useful overview of a number of bonding agents known in the field of engineering, presents Dreborg et al. (see Critical Reviews in Therapeutic Drug Carrier Systems, 6(4):315-165, (1990), see, in particular, cc.317-320).

Paglierani peptides and PYY agonists may also have the General formula

where D is the residue of a peptide or agonist PYY;

X is a group that removes an electron;

Y and Y' independently represented by O or S;

(n) is zero (0) or a positive integer, preferably from 1 to approx the positive 12;

R₁and R₂independently selected from the group consisting of H, C_1-6-Akilov, arrow, substituted arrow, aralkyl, heteroalkyl, substituted heteroalkyl and replaced With_1-6-Akilov;

R₃almost neoantigenic polymer With_1-12is unbranched or branched alkyl or substituted alkyl, C_5-8-cycloalkyl or substituted cycloalkyl, carboxyethyl, carboalkoxylation, dialkylaminoalkyl, phenylalkyl, vinylaryl or

and R₄and R₅independently selected from the group consisting of H, C_1-6-Akilov, arrow, substituted arrow, aralkyl, heteroalkyl, substituted heteroalkyl and replaced With_1-6-Akilov or they together form a cyclic₅-C₇-structure. Cm. U.S. patent No. 6127355.

Typical alkyl groups include C_1-6is an alkyl group, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl etc.

Preferred aryl groups include_6-14-aryl groups, and typically include phenyl, naftalina, fluoroanilino, phenanthroline and anthracyline group.

Typical alkyl-substituted aryl groups include any of the above aryl gr is PP, replaced by any of the C_1-6-alkyl groups, including group Ph(CH₂)_nwhere n=1-6, for example, toluene, o-, m - and p-xilion, ethylphenyl, 1-propylphenyl, 2-propylphenyl, 1-butylphenol, 2-butylphenyl, tert-butylphenyl, 1-pentylphenol, 2-pentylphenol, 3-pentylphenol.

Typical cycloalkyl groups include_3-8cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptyl and cyclooctyl group.

Typical groups that removes an electron, include O, NR₁, S, SO and SO₂where R₁defined above.

The PYY antagonists

Also considered the use of receptor antagonist Y. receptor Antagonist Y is a substance (usually a ligand)that binds to the receptor and Y blocks the physiological effect of the agonist receptor Y (such as PYY, NPY or PP (see Tables 1-3 above). These antagonists can be either a peptide antagonists, or ones antagonists PYY, NPY or PP.

Peptide antagonist includes modifications, mutants, fragments and/or variants of the natural amino acid sequence of peptides PYY, NPY or PP (obtained, for example, by deletions, substitutions, amino acid deletions, insertions and modifications of N-terminal amino - and/or C-terminal carboxyl group)that result in clicks the application of peptide, acting as a receptor antagonist Y. in Addition, the amino acid sequence PYY, NPY or PP can be merged or chimeric proteins, which act as receptor antagonists Y. these peptides can also be modified by such processes as lipiduria, tahilramani, amidation, glycosylation, acylation, sulfation, phosphorylation, acetylation and cyclization.

Many of the ones Y receptor antagonists are well known in the field of engineering, and they intend to use in this invention. (See Table 5, below). Any known ones antagonists PYY, NPY or PP can be used in this invention.

TABLE 5 - the Antagonist, PYY and NPY

Examples of Y receptor antagonists include, but are not limited to the following connections:

VW

Reference: see Berglund, M.M. Biochem. Pharmacol., 60(12):1815-22, December 15, 2000

SR120819A

1-[2-[2-(2-aftershool)-3-phenylpropionamide]-3-[4-N-[4-(dimethylaminomethyl)-CIS-cyclohexylmethyl]amidino]phenyl]propionyl] pyrrolidine, (S, R)-stereoisomer

Reference: see Berglund, M.M. Biochem. Pharmacol., 60(12):1815-22, December 15, 2000

BIIE0246

(S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-Acadians[b,e]azepin-11-yl]-1-piperazinil]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazole-4-yl]ethyl]-arginine

Reference: Malmstrom, Life Sci., 69(17):1999-2005, September 14, 2001

BIBP 3226

[(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide] and the recently described peptide structure [Ile-GLU-PRO-ORN-Tyr-Arg-Leu-Arg-Tyr-NH2, cyclic(2,4'),(2',4)-diamid].

Reference: see Doods, N. N. J.Pharmacol. Exp.Ther., 275(1): 136-42, October 1995

BIBP 3435

Reference: see Lundberg J. M., ModinA., Br.J. Pharmacol., 116(7):2971-82, December 1995

H 394/84

dimethyl ester of 1,4-dihydro-4-[3-[[[[3-[Spiro(inden-4,1'-piperidine-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid

Reference: see R. E. Malmstrom, Eur. J. Pharmacol., 418(1-2):95-104, April 20, 2001

H 409/22

(2R)-5-([amino(imino)methyl]amino)-2-[(2,2-diphenylacetyl)amino]-N-[(IR)-1-(4-hydroxyphenyl)ethyl]-pentanone

Reference: see Malmstrom R. E. Life Sci., 69(17): 1999-2005, September 14, 2001

1229U91

Reference: see Schober D. A., Peptides, 19(3):537-42, 1998

L-152804

Reference: see Kanatani A. Biochem. Biophys. Res. Commun., 272(1): 169-73, may 27, 2000

Aminoalkyl-substituted pyrazolo-[1,5,-a]-1,5-pyrimidines and pyrazolo-[1,5-a]-1,3,5-triazine

Reference: U.S. Patent No. 6372743

Alkyl and cycloalkyl derivatives of 1,4-dihydropyridines (e.g., dimethyl ester

1,4-dihydro-2,6-dimethyl-4-[4-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino]carbonyl]amino]butyl] - for 3,5-pyridine-carboxylic acid)

Reference: U.S. Patent NO. 6444675

Derivatives of [4-(3-substituted phenyl)-1,4-dihydropyridines

Reference: U.S. Patent No. 535503

Derivatives of ester dimethyl 4-phenyl-1,4-dihydropyridines for example,

1,4-dihydro-4-[3-[[2-[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino]-3,4-dioxo-1-cyclobutene-1-yl]amino]phenyl]-2,3-dimethyl-3,5-pyridinedicarboxylic acid

Reference: U.S. Patent NO. 6432960

Receptor antagonist Y on the basis of a substituted amide such as:

N-(4-diethylamino-phenyl)-2-phenyl-2-pyridin-4-yl-ndimethylacetamide;

2-(4-forfinal)-2-pyridin-4-yl-N-(3,4,5,6-tetrahydro-2H-[1,2']-bipyridinyl-5'-yl)-ndimethylacetamide;

2-phenyl-2-pyridin-4-yl-N-(3,4,5,6-tetrahydro-2H-[1,2']-bipyridinyl-5'-yl)-ndimethylacetamide;

N-(4-diethylamino-phenyl)-2-phenyl-2-pyridin-2-yl-ndimethylacetamide;

N-(6-diethylamino-pyridine-3-yl)-2,2-diphenylacetamide;

N-(4-diethyl-sulfamoyl-phenyl)-2-phenyl-2-pyridin-4-yl-ndimethylacetamide;

2,2-diphenyl-N-(6-pyrrolidin-1-yl-pyridine-3-yl)-ndimethylacetamide;

2,2-diphenyl-N-(3,4,5,6-tetrahydro-2H-[1,2']-bipyridinyl-5'-yl)-ndimethylacetamide;

N-[6-(2,5-dimethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2,2-diphenyl-ndimethylacetamide;

N-(4-diethylcarbamoyl-phenyl)-2,2-diphenyl-ndimethylacetamide and

N-(4-dimethylsulphamoyl-phenyl)-2,2-diphenyl-ndimethylacetamide.

Reference: U.S. Patent No. 6407120 Carbazolyl receptor antagonist Y, such as:

2-dimethylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

3 diethylamino-N-(9-ethyl-N-carbazole-3-yl)-propionamide;

N-(9-ethyl-N-carbazole-3-yl)-2-fluoro-benzamide;

4-dimethylamino-N-(9-ethyl-N-carbazole-3-yl)-butyramide;

N-(9-ethyl-N-carbazole-3-yl)--hydroxy-2,2-diphenyl-ndimethylacetamide;

N-(9-ethyl-N-carbazole-3-yl)-2-hydroxy-2-methyl-propionamide;

N-(9-ethyl-N-carbazole-3-yl)-2-hydroxy-2-methyl-butyramide;

N-(9-ethyl-9H-carbazole-3-yl)-2-hydroxy-2-phenyl-propionamide;

(R)-N-(9-ethyl-N-carbazole-3-yl)-2-hydroxy-2-phenyl-propionamide;

2-bromo-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide and

3-dimethylamino-N-(9-ethyl-N-carbazole-3-yl)-propionamide.

2-[bis-(2-hydroxyethyl)-amino]-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

2 benzylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

3 diphenylamino-N-(9-ethyl-9H-carbazole-3-yl)-propionamide and

N-(9-ethyl-N-carbazole-3-yl)-3-(4-piperidine-1-ylmethyl-phenoxy)-propion amide;

N-(9-ethyl-N-carbazole-3-yl)-3-[methyl-(1,2,3,4-tetrahydro-naphthalene-2-yl)-amino]-propionamide;

N-(9-ethyl-N-carbazole-3-yl)-3-(quinoline-7-yloxy)-propionamide and

2-[bis-(2-hydroxyethyl)-amino]-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide.

3-bromo-N-(9-ethyl-N-carbazole-3-yl)-propionamide;

N-(9-isopropyl-N-carbazole-3-yl)-triptorelin;

4-dimethylamino-N-(9-ethyl-N-carbazole-3-yl)-N-methyl-butyramide;

N-(9-methyl-N-carbazole-3-yl)-triptorelin;

1-hydroxy-cyclopropanecarbonyl acid-(9-ethyl-N-carbazole-3-yl)-amide and

2-(4-chloro)-benzylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide.

2-(4-fluoro)-benzylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

(R)-N-(9-ethyl-N-carbazole-3-yl)-2-(1-phenyl-ethylamino)-ndimethylacetamide;

(R)-N-(9-ethyl-N-carbazole-3-yl)-2-(1-(4-chloro)-phenyl-ethylamino)-ndimethylacetamide;

2-(3-d is ethylamino-2-hydroxy-propylamino)-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

2-(benzyl-isopropyl-amino)-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

N-3-bromo-(9-ethyl-9H-carbazole-6-yl)-triptorelin;

N-(9-ethyl-6-formyl-N-carbazole-3-yl)-triptorelin;

N-(9-ethyl-6-hydroxymethyl-N-carbazole-3-yl)-triptorelin;

N-(9-ethyl-N-carbazole-3-yl)-methanesulfonamide;

N-(9-ethyl-N-carbazole-3-yl)-chloromethanesulfonyl;

2-bromo-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide and

3-dimethylamino-N-(9-ethyl-N-carbazole-3-yl)-propionamide.

2-[bis-(2-hydroxy-ethyl)-amino]-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

2 benzylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

3 diphenylamino-N-(9-ethyl-N-carbazole-3-yl)-propionamide;

N-(9-ethyl-9H-carbazole-3-yl)-3-(4-piperidine-1-ylmethyl-phenoxy)-propionamide;

N-(9-ethyl-N-carbazole-3-yl)-3-[methyl-(1,2,3,4-tetrahydro-naphthalene-2-yl)-amino]-propionamide;

N-(9-ethyl-N-carbazole-3-yl)-3-(quinoline-7-yloxy)-propionamide;

2-[bis-(2-hydroxy-ethyl)-amino]-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

3-bromo-N-(9-ethyl-N-carbazole-3-yl)-propionamide and

N-(9-isopropyl-N-carbazole-3-yl)-ndimethylacetamide.

4-dimethylamino-N-(9-ethyl-N-carbazole-3-yl)-N-methyl-butyramide;

N-(9-methyl-N-carbazole-3-yl)-triptorelin;

1-hydroxy-cyclopropanecarbonyl acid-(9-ethyl-N-carbazole-3-yl)-amide;

2-(4-chloro)-benzylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide and

2-(4-fluoro)-benzylamino-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide.

(R)-N-(9-ethyl-N-carbazole-3-yl)-2-(1-phenyl-ethylamino)-and Itemid;

(R)-N-(9-Ethyl-N-carbazole-3-yl)-2-(1-(4-chloro)-phenyl-ethylamino)-ndimethylacetamide;

(R)-, (S)- or a mixture of (R)- and

(S)-2-(3-diethylamino-2-hydroxy-propylamino)-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

(S)-N-(6-tert-butyl-9-ethyl-N-carbazole-3-yl)-2-(3-diethylamino-2-hydroxy-propylamino)-ndimethylacetamide,

2-(benzyl-isopropyl-amino)-N-(9-ethyl-N-carbazole-3-yl)-ndimethylacetamide;

N-3-bromo-(9-ethyl-N-carbazole-6-yl)-triptorelin;

N-(9-ethyl-6-formyl-N-carbazole-3-yl)-triptorelin and

N-(9-ethyl-6-hydroxymethyl-N-carbazole-3-yl)-triptorelin.

N-(9-ethyl-N-carbazole-3-yl)-methanesulfonamide and

N-(9-ethyl-N-carbazole-3-yl)-chloromethanesulfonyl.

Reference: see U.S. Patent No. 6399631 Various dihydropyridine derivatives:

Reference: see U.S. Patent No. 4829076

Cyanoguanidine derivatives of 4-(3-substituted phenyl)-1,4-dihydropyridine

Reference: see U.S. Patent No. 6001836

Amide derivatives which are antagonists of the receptor Y5 NPY

Reference: see U.S. Patent No. 6410792

Associated with thiourea pieperazinove and piperidine derivatives of 4-phenyl-1,4-dihydropyridines, such as: dimethyl ester of 1,4-dihydro-4-[3-[[[[3-[4-(3-methoxyphenyl) piperidinyl]propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid, dimethyl ester,

1,4-dihydro-4-[3-[[[[3-(4-phenylpiperidine)propyl]amino]coronation]amino]phenyl]-2,6-dimethyl-3,5-pyridine-di is arbonboy acid and

dimethyl ester

1,4-dihydro-4-[4-[[[[3-(4-cyclohexyl-1-piperazinil)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid.

dimethyl ester

1,4-dihydro-4-[4-fluoro-3-[[[[3-(4-phenylpiperidine)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid,

dimethyl ester

1,4-dihydro-4-[3-[[[[3-(4-methyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-forfinal)-2,6 - dimethyl-3,5-pyridine-dicarboxylic acid,

dimethyl ester

1,4-dihydro-4-[3-[[[[[3-(4-ethyl-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-forfinal]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid,

dimethyl ester

1,4-dihydro-4-[3-[[[[[3-(4-propyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-forfinal]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid,

dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-1,1-dimethylethyl)-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-forfinal]-2,6-dimethyl-3,5-pyridinedicarboxylic acid,

dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(1-methylethyl)-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-forfinal]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid and

dimethyl ester

1,4-dihydro-4-[4-[[[[3-(4-cyclohexyl-1-piperazinil)propyl]amino]carbonothioyl]amino]-4-forfinal]-2,6-dimethyl-3,5-pyridine-dicarboxylic acid.

the premise: see U.S. patent No. 6391881

New arylsulfonamides and sulfamide connection

Reference: see U.S. Patent No. 6391877

Amine and amide derivatives receptor antagonist Y, such as:

Amino-6-[(2-perpenicular)amino]-N-[CIS-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthenyl]-(2S)-hexanamide bis-hydrochloride,

N-[5-amino-6-[[CIS-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-]-naphthalenyl]amino]hexyl]-2-forbindelsesfaneblad Tris-hydrochloride,

N-[5-amino-6-[CIS-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]amino]hexyl]-2-forbindelsesfaneblad Tris-hydrochloride,

(2S)-2-(acetylamino)-6-[(2-perpenicular)amino]-N-[CIS-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinyl methyl)-2-naphthenyl]hexanamide bis-hydrochloride,

(2S)-2-(acetylamino)-6-[(2-perpenicular)amino]-N-[CIS-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthenyl]hexanamide bis-hydrochloride,

3-[(phenylsulfonyl)amino]-N-[CIS-1,2,3,4-tetrahydro-6-fluoro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidinyl]bis-triptorelin,

4-oxo-1-phenyl-N-[CIS-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1,3,8-diazaspiro[4.5]-decane-8-ndimethylacetamide bis-hydrochloride, TRANS-N-[2-(4-forfinal)-3-(3-pyridinyl)propyl]-4-[((2-fluoro-phenylsulfonyl)amino)methyl]-1-cyclohexanone hydrochloride, TRANS-N-[[[[[2-(4-forfinal)-3-(3-pyridinyl)propyl]amino]methyl]-4-cyclohexyl] methyl]2-perbenzoic ltname bis-hydrochloride.

Reference: see U.S. Patent No. 6380224.

Alkylenediamine-substituted pyrazole-(1,5-a)-1,5-pyrimidines and pyrazolo-(1,5-a) 1,3,5-triazine, such as:

[2-{2-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethylamino}-butane-1-ol;

N-2-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethyl}-N'-methyl-cyclohexane-1,4-diamine;

N-{2-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo[1,5-a]-pyrimidine-7-ylamino]-ethyl}-N'-ethyl-cyclohexane-1,4-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(4-(morpholine-4-yl-cyclohexyl)-ethane-1,2-diamine;

4-{2-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethylamino}cyclohexanol;

3-{2-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethylamino}-propane-1,2-diol;

N-{2-[3(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethyl}-N'-isobutyl-cyclohexane-1,4-diamine;

N-{2-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethyl}-N-isobutyl-cyclohexane-1,4-diamine;

4-{2-[3-(2,6-dichloro-4-ethoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-1-methyl-ethylamino}cyclohexanol;

2-{2-[3-(2,6-dichloro-4-ethoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-ethylamino}cyclohexanol;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(4,4,4-tripto the-butyl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-ethoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2,2,2-triptorelin)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2-trifluoromethyl-cyclohexyl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(4-trifluoromethyl-cyclohexyl)-ethane]-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2,2-debtor-ethyl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2-fluoro-1-methyl-ethyl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2-fluoro-cyclohexyl)-ethane-1,2-diamine.

N-[3-(2,6-dichlorophenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-ethyl-piperidine-5-a]-pyrimidine-7-yl]-N-(2,2,6,6-tetramethyl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-19-piperidine-4-yl-ethane-1,2-diamine;

N-[3-(2,6-dichlorophenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-ethyl-piperidine-3-yl)-ethylamine-1,2-diamine;

N-(1-benzyl-pyrrolidin-3-yl)-N'-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-ethane-1,2-diamine;

N-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-pyrimidine-2-yl-ethane-1,2-diamine;

N-(1-benzylpiperidine-4-yl)-N'-[3-(2,4-dichloro-6-methoxyphenyl)-2,5-diethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-ethane-1,2-diamine;

N-(1-benzylpiperidine-4-yl)-N'-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo[1,5-a]-pyrimidine-7-yl]-ethane-1,2-diamine;

N-[3(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-methyl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-ethyl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-isopropyl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2,2,6,6-tetramethyl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-ethyl-piperidine-3-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-piperidine-4-yl-ethane-1,2-diamine;

N.sup.2-(1-benzyl-piperidine-4-yl)-N'-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-propane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyridin-3-yl-methyl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-Dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyridine-4-ylmethyl-piperidine-4-yl)-ethane-1,2-diamine;

3,5-dichloro-4-12,5-dimethyl-7-2-(1-phenyl-pyrrolidin-3-ylamino)-ethylamino]-pyrazolo-[1,5-A]-pyrimidine-3-yl]-phenol;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]- pyrimidine-7-yl]-N'-(1-pyridin-2-yl-methyl-piperidine-4-yl)-ethane-1,2-diamine;

3,5-dichloro-4-(2,5-dimethyl-7-[2-(1-pyrimidine-2-yl-piperidine-4-ylamino)-ethylamino]-irazola-[1,5-a]-pyrimidine-3-yl}-benzonitrile;

N-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-(1-benzyl-piperidine-4-yl)-N'-[3(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-ethane-1,2-diamine;

N-[3-(2,6-dichloro-phenyl)-5-ethyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-phenyl)-5-isopropyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,4-dichloro-phenyl)-5-isopropyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-5-isopropyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N2-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-5-ethyl-2-methylpyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2-methyl-5-propyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-5-ethyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[-(2,6-dichloro-phenyl)-2-methyl-5-propylpyrazole-[1,5-a]-pyrimidine-7-yl-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-phenyl)-2-methyl-5-propyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N2-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dichlorophenyl)-5-ethyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]

-N.sup.2-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[5-ethyl-2-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[5-ethyl-2-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dichloro-4-ethinyl-phenyl)-2,5-dimethylpyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[2-methyl-5-propyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[2,[5-dimethyl-3-(2,4,6-trimetilfenil)-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-(1-pyridin-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dimethyl-phenyl)-5-ethyl-2-methyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dimethyl-phenyl)-2-methyl-5-propyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,6-dimethyl-phenyl)-2-methyl-5-propyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N2-(1-pyrimidine-2-yl-piperidine-4-yl)-propane-1,2-diamine;

N-[3-(2,6-dimethyl-phenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-reparacin-4-yl)-propane-1,2-diamine;

N-[3-(2,4-dimethyl-phenyl)-5-ethyl-2-methyl-pee the Asolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine;

N-[3-(2,4-dimethyl-phenyl)-2-methyl-5-propyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(1-pyrimidine-2-yl-piperidine-4-yl)-ethane-1,2-diamine and

[1-[4-(1-{[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-ylamino]-methyl]-propylamino)piperidine-1-yl]-Etalon.

N-[2,5-dimethyl-3-(2,4,6-trimetilfenil)-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-[2-(4-methoxyphenyl)-ethyl]-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-[2-(4-methoxyphenyl)-ethyl]-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N'-[2-(3-ethoxy-4-methoxyphenyl)-ethyl]-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-[2-(4-ethoxy-3-methoxyphenyl)-ethyl]-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo-[1-a]-pyrimidine-7-yl]-N'-(1,2,3,4-tetrahydro-naphthalene-2-yl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2-pyridin-2-yl-ethyl)-ethane-1,2-diamine;

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2-pyridin-3-yl-ethyl)-ethane-1,2-diamine and

N-[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo-[1,5-a]-pyrimidine-7-yl]-N-(2-pyridin-4-yl-ethyl)-ethane-1,2-diamine.

Reference: U.S. Patent No. 6372743

Serosanguineous derivative of Y antagonist, such as:

2-(3-chlorpropyl)-2-phenyl-1,3-dioxolane,

2-(3-chlorpropyl)-2-(4-methoxyphenyl)-1,3-dioxolane,

2(3-chlorpropyl)-2-(4-phenoxyphenyl)-1,3-dioxolane,

2-(3-chlorpropyl)-2-(4-bromophenyl)-1,3-dioxolane,

2-(3-chlorpropyl)-2-(4-chlorophenyl)-1,3-dioxolane,

N-3-chloropropyl-N-methylbenzeneethanamine hydrochloride

N-(3-chloropropyl)-N-(phenylmethyl)benzoylmethylene hydrochloride

N-(2-hydroxyethyl)-N-methylbenzeneethanamine,

chloro-1-(4-phenoxyphenyl)-Etalon,

3-chloro-1-(4-phenoxyphenyl)-propanone,

1'-[3-(4-phenoxyphenyl)-3-oxopropyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he hydrochloride

1'-[3-(4-bromophenyl)-3-oxopropyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he],

1'-[2-[(1,1'-biphenyl)-4-yl]-2-oxoethyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he],

1'-[2-(4-bromophenyl)-2-oxoethyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he],

1'-[2-(4-phenoxyphenyl)-2-oxoethyl]Spiro[isoquinoline-1-(2H-4'-piperidine-3-(4H)-he], hydrochloride

1'-[2-[bis(phenylmethyl)amino]ethyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] dihydrochloride,

1'-(4-phenyl-4-oxobutyl)Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)he] hydrochloride

1'-[4-(4-methoxyphenyl)-4-oxobutyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] hydrochloride

1'-[4-(4-phenoxyphenyl)-4-oxobutyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] hydrochloride

1'-[4-(4-bromophenyl)-4-oxobutyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he],

1'-[4-(4-chlorophenyl)-4-oxobutyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] hydrochloride

1'-[2-[(1,1'-biphenyl)-3-yl]-2-oxoethyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] guide chlorid,

1'-[3-[(1,1'-biphenyl)-4-yl]-3-oxopropyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] hydrochloride

1'-[4-(1,1'-biphenyl)-4-yl]-4-oxobutyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] hydrochloride

1'-[2-(1,1'-biphenyl)-4-yl]-2-hydroxyethyl]Spiro[isoquinoline-1-(2H)-4'-piperidine-3-(4H)-he] hydrochloride.

Reference: see U.S. Patent No. 6348472

The triazine derivative of Y receptor antagonists, such as:

N1-{[4-({[4-(isopropylamino)-6-(methylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4-(ethylamino)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate)-6-(isopropylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonic

N1-{[4-({[4,6-di(isopropylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4-(isopropylamino)-6-(propylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl-3-methyl-1-naphthalenesulfonate,

N1-[4-([4-(butylamino)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-[4-([4-cyclobutylamine)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl] methyl-1-naphthalenesulfonate,

N1-[4-([4-(cyclopropylamino)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-[4-([4-(isopropylamino)-6-(pentylamine)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]met the l-1-naphthalenesulfonate,

N1-[4-([4-[(2-cyanoethyl)amino]-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-[4-([4-[(2-hydroxyethyl)amino]-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-(4-[(4-(isopropylamino)-6-((2-methoxyethyl)amino]-1,3,5-triazine-2-yl]amino)methyl]cyclohexylmethyl)-1-naphthalenesulfonate,

N1-(4-[(4-(isopropylamino)-6-[(3-methoxypropyl)amino]-1,3,5-triazine-2-ylamino)methyl]cyclohexylmethyl)-1-naphthalenesulfonate,

N1-{[4-({[4-}[2-(dimethylamino)ethyl]amino}-6-(isopropylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4-[3-(1H-1-imidazolyl)propyl]amino-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-({4-[({4-(isopropylamino)-6-1-(4-methoxyphenethyl)amino]-1,3,5-triazine-2-yl}amino)methyl]cyclohexyl}methyl)-1-naphthalenesulfonate,

N1-{[4-({[4-(dimethylamino)-6-(isopropylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4-[ethyl(methyl)amino]-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-[4-([4-(diethylamino)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexylmethyl-1-naphthalenesulfonate,

N1-[4-([4-(isopropylamino)-6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-(4-[4-(isopropylamino)-6-[(2S)-2-(methoxymethyl)tetrahydro-1H-1-pyrrolyl]-1,3,5-triazine-2-ylamino)methyl]cyclohexyl methyl)-1-naphthalenesulfonate,

N1-{[4-({[4-(isopropylamino)-6-piperidino-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4-(isopropylamino)-6-(2-methylpiperidino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-[4-([4-(isopropylamino)-6-morpholino-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-{[4-({[4-[(2R,6S)-2,6-dimethyl-1,4-oxazine-4-yl]-6-(isopropylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4-[(2-hydroxyethyl)(methyl)amino]-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-naphthalenesulfonate,

N1-{[4-({[4-(4-acetylpiperidine)-6-(isopropylamino)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-{[4-({[4-(isopropylamino)-6-(4-isopropylpiperazine)-1,3,5-triazine-2-yl]amino}methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-(tert-butyl)-1-benzosulfimide,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzosulfimide,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-2-methoxy-5-methyl-1-benzosulfimide,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-2-fluoro-1-benzosulfimide,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-2-methyl-1 be solarpanel,

N3-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-3-pyridinesulfonamide,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-methoxy-1-benzosulfimide,

N5-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-2,4-dimethyl-1,3-oxazol-5-sulfonamide,

N2-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-2-thiophenesulfonyl,

N4-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-methyl-1H-4-imidazolecarboxamide,

N1-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-methyl-1-benzosulfimide,

N5-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-2,1,3-benzothiadiazole-5-sulfonamide,

N8-[4-([4,6-di(ethylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-8-chinaincorporated-yl]aminomethyl)cyclohexyl]methylmethane-sulfonamide,

N1-[4-([4-(isopropylamino)-6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-pyrrolidinecarbonyl,

N4-[4-([4-(isopropylamino)-6-morpholino-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-morpholinoethyl,

N1-[4-([4-(isopropylamino)-6-piperidino-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-1-piperidinylidene,

N1-[(4-[(4,6-deathraider-1H-1-pyrrolyl-1,3,5-triazine-2-yl)amino]methylcyclohexyl)methyl]-4-(tert-butyl)-1-benzosulfimide,

N-cyclopropyl-N'-[4-([4-(cyclopropylamino is)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]metilsulfate,

N'-[4-([4-(cyclopropylamino)-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-N,N-dimethylsulfone,

N1-{[4-({[4-chloro-6-(isopropylamino)-1,3,5-triazine-2-yl]amino} methyl)cyclohexyl]methyl}-1-naphthalenesulfonate,

N'-[(4-[(4,6-dimorpholino-1,3,5-triazine-2-yl)amino]methylcyclohexyl) methyl]-N,N-[dimethylsulfone,

N1-[4-([4-chloro-6-(isopropylamino)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-(tert-butyl)-1-benzosulfimide,

N1-[4-([4-(cyclopropylamino)-6-tetrahydro-1H-1-pyrrolyl-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzosulfimide,

N'-((4-(((4,6-dichloro-1,3,5-triazine-2-yl)amino)methyl)cyclohexyl)methyl)-N,N-dimethylsulfone,

N1-[(4-[(4,6-deathraider-1H-1-pyrrolyl-1,3,5-triazine-2-yl)amino]methylcyclohexyl)methyl]-2-methoxy-5-methyl-1-benzosulfimide,

N1-[4-([4-(cyclopropylamino)-6-(2-pyridyl)-1,3,5-triazine-2-yl]aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzosulfimide,

N1-[4-(aminomethyl)cyclohexyl]methyl-4-fluoro-1-benzosulfimide,

N2,N4-diethyl-6-[5-(1H-1-pyrazolyl)pentyl]-1,3,5-triazine-2,4,6-triamine

N2,N4-diethyl-N6-[3-(1H-1-imidazolyl)propyl]-1,3,5-triazine-2,4,6-triamine

N2,N4-diethyl-N6-(2-pyridylmethyl)-1,3,5-triazine-2,4,6-triamine

Reference: U.S. Patent No. 6340683

Tricyclic compounds of Y receptor antagonists, such as:

TRANS-N2-(4-dimethylaminocarbonylmethyl)cyclohexyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][13][thiazol-2-amine;

1-Aza-9-fluoro-4,5-dihydro-2-{5-(dimethylaminomethyl-amino)pentyl} amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-2-(5-(2-forfinal)sulfonylamino)pentylamine-4,5 - dihydro-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(1-naphthyl)sulfonylamino)-pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(4-(methanesulfonamido)-butyl)amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(4-(dimethylaminomethylene)butyl) amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-2-(4-(2-forfinal)sulfonylamino)butylamino-4,5-dihydro-3-thia-benzo[e]azulene-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(4-((2(S)-methoxymethyl)-pyrrolidin-1-yl)sulfonyl)phenylamino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(methylsulfonylamino)-pentyl)amino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(methylsulfonylmethyl) cyclohexyl)amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(2,4-differenl)sulfonylamino) pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-isopropylacrylamide)-pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(diethylaminoethylamine)pentyl) amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(2-methoxy-5-were)sulfonylamino) pentylamine-3-thia-benzo[e]azulene;

1-Aza-2-(5-benzylmethylamine)pentylamine-9-fluoro-4,5-dihydro-3-thia - benzo[e]azulene;

1-Aza-2-(5-(3,4-di is terphenyl)sulfonylamino)pentylamine-9-fluoro-4,5-dihydro-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(4-methoxyphenyl)sulfonylamino) pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(2-thienyl)sulfonylamino)-pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-2-(5-(2-triptorelin)sulfonylamino)pentylamine-4,5-dihydro-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-2-(5-ethylsulfonyl)pentylamine-4,5-dihydro-3-thia-benzo[e]azulene;

1-Aza-2-(4-diethylaminoethylamine)butylamino-9-fluoro-4,5-dihydro-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(1-Mei-4-yl)sulfonylamino) pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(3,5-dimethylisoxazol-4-yl)sulfonyl-amino)pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-aminosulfonyl)pentylamine-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-2-(4-(2-forfinal)sulfoaluminate)cyclohexyl-amino-4,5-dihydro-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-{4-(4-methoxyphenyl)sulfoaluminate}cyclohexylamino-3-thia-benzo[e]azulene;

TRANS-N2-(4-(2,6-differentiality)aminomethyl)cyclohexyl-9-fluoro - 5,6-dihydro-4H-benzo[6,7]cyclohepta[d]-[1,3]-thiazole-2-amine;

TRANS-1-Aza-2-{4-benzylmethylamine}cyclohexylamino-9-fluoro-4,5-dihydro-3-thia-benzo[e]azulene;

TRANS-N2-(4-(2-thienylmethyl)aminomethyl)cyclohexyl-9-fluoro-5,6-di-hydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

TRANS-N2-(4-ethylsulfinylmethyl)is illogical-9-fluoro-5,6-dihydro-4H-benzo[6,7] cyclohepta[d][1,3]thiazole-2-amine;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-{4-(1-methylimidazol-4-yl)sulfonyl-aminomethyl} cyclohexylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-{4-(3,5-dimethylisoxazol-4-yl)sulfoaluminate}cyclohexylamino-3-thia-benzo[e]azulene)cyclohexyl-amino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-diethylaminoethylamine)cyclo-hexylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(4-methoxyphenyl)sulfonylamino)qi-chlorexidine-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(2-thienyl)sulfonylamino)cyclo-hexylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(2,2,2-Cryptor-ethyl)sulfonylamino) cyclohexylamino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(4-(2,2,2-triptorelin)-sulfonylamino)butyl-amino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-2-{4-(3,4-differenl)sulfonyl-aminomethyl} cyclo-hexylamino-4,5-dihydro-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-2-{4-triftormetilfullerenov }cyclohex-Salamina-4,5-dihydro-3-tiebens[e]azulene;

TRANS-1-Aza-9-fluoro-2-{4-(2-fluoro)phenylcarbonylamino}-cyclohexylethylamine-4,5-dihydro-3-thia-benzo[e]azulene;

TRANS-N2-(4-methylsulfonylamino)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine: a Mixture of TRANS-N2-(4-amino)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine of digid is ochloride;

TRANS-N2-(4-aminosulfonyl)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

TRANS-N2-(4-amino)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

TRANS-N2-(4-aminosulfonyl)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine:

6-bromo-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-he;

N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)-5-bromopentane;

[1-5-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]-thiazol-2-yl)amino]-5-oxopent-1,2-Trisagion-2-FMD;

N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)-5-aminopentanoic;

N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)-5-[(methylsulphonyl)amino]pentanone;

TRANS-N2-(4-aminosulphonylphenyl)cyclohexyl-4,5-dihydro-benzo [2,3]oxepin[4,5-d][1,3]thiazole-2-amine;

TRANS-N2-(4-methylsulfonylmethyl)cyclohexyl-4,5-dihydro-benzo [2,3]oxepin[4,5-b][1,3]thiazole-2-amine;

TRANS-1-Aza-4,5-dihydro-2-{4-(2-methoxy-5-methyl)phenyl-sulfonylamino-methyl}cyclohexylamino-6-oxa-3-thia-benzo[e]azulene;

N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]-thiazol-2-yl)-5-[(2-methoxy-5-were)sulfonyl]-aminopentanoic;

N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]-thiazol-2-yl)-5-aminopentanoic;

TRANS-N2-(4-methylsulfonylamino)cyclohexyl the Teal-4,5-dihydro-benzo [2,3]oxepin[4,5-d][1,3]thiazole-2-amine;

TRANS-1-Aza-4,5-dihydro-2-{4-(2-methoxy-5-were)-sulfonylamino}cyclohexylethylamine-6-oxa-3-thia-benzo[e]azulene;

TRANS-N2-(4-ethylsulfonyl)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-{4-isopropylbenzylamine}cyclohex Silmarillion-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(3-pyridylsulfonyl)cyclohexyl)amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(5-(3-pyridyl)sulfonylamino)pentylamine-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-(4-(3-pyridyl)sulfonylamino)butylamino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-{2-(2-methylsulfonylamino)ethoxy}ethyl-amino-3-thia-benzo[e]azulene;

1-Aza-9-fluoro-4,5-dihydro-2-{2-[2-(2-methoxy-5-were)sulfonylamino] ethoxy} ethylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(3-pyridyl)sulfoaluminate) cyclohexylamino-3-thia-benzo[e]azulene;

TRANS-N2-(4-ethylsulfonyl)cyclohexylmethyl-8-methoxy-4,5-dihydro-benzo[2,3] oxepin[4,5-C1] [[1,3]thiazole-2-amine;

TRANS-1-Aza-4,5-dihydro-8-methoxy-2-{4-methylsulphonyl-amino)cyclo-hexylamino-6-oxa-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-[{4-(3-pyridyl)sulfonylamino}cyclo-hexylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-4,5-dihydro-9-methoxy-2-{4-methylsulfonylamino} cyclohexylethylamine-oxa-3-thia-benzo[e]azulene;

TRANS-N2-(4-ethylsulfonyl)cyclohexylmethyl-9-methoxy-4,5-dihydro-benzo[2,3]oxepin[4,5-d][1,3]thiazole-2-amine;

TRANS-N2-(4-methylsulfonylamino)cyclohexylmethyl-7-methoxy-4,5-dihydro-benzo[2,3]oxepin[4,5-d][1,3]thiazole-2-amine hydrochloride;

TRANS-1-Aza-4,5-dihydro-7-methoxy-2-{4-dimethylaminomethylene} cyclohexylethylamine-6-oxa-3-thia-benzo[e]azulene;

TRANS-N2-(4-dimethylphenylimino)cyclohexylmethyl-9-fluoro-5,6-dihyd-ro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

TRANS-N2-(4-ethoxycarbonylphenyl)cyclohexylmethyl-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine hydrochloride;

1-Aza-9-fluoro-4,5-dihydro-2-(2-(2-isopropylaniline)ethoxy)ethyl-amino-3-thia-benzo[e]azulene;

2-(4-methylsulfonylamino)cyclohexylamino-4H-chromeno[4,3-d] thiazole;

TRANS-1-Aza-4,5-dihydro-8-methoxy-2-(4-methylsulfonylamino)cyclo-hexylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-4,5-dihydro-8-methoxy-2-(4-methylsulfonylamino)CEC-ohexylamine-3-thia-benzo[e]azulene;

TRANS-1-Aza-4,5-dihydro-2-(4-isopropylaminomethyl)cyclo-hexylamino-8-methoxy-3-thia-benzo[e]azulene;

TRANS-1-Aza-4,5-dihydro-2-(4-methylsulfonylmethyl)cyclohexyl-amino-7-methoxy-3-thia-benzo[e]azulene;

TRANS-1-Aza-4,5-dihydro-2-(4-ethylcarbodiimide)cyclohexylamino-9-fluoro-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(4-morpholinyl)sulfonylamino-methyl)cyclohexylamino-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(2-methoxy)ethoxy-carbylamine-methyl)cyclohexylamino-3-thia-benzo[e]azulene-2-methoxyethyl-N-(t4-(9-fluoro-5,6-dihydro-4H-benzo[6,7]-cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}methyl)-carbamate;

tert-butyl N-[(4-{[(benzoylamine)carbothioic]amino}cyclohexyl)methyl]carbamate;

tert-butyl N-({4-[(aminocarbonyl)amino]cyclohexyl}-methyl)]carbamate;

6-bromo-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-he;

tert-butyl N-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta-[D][1,3]thiazol-2-yl)amino]cyclohexyl}methyl)-carbamate;

TRANS-N2-[[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(2-methoxy)ethoxycarbonyl-methyl)cyclohexylamino-3-thia-benzo[e]azulene-2-methoxyethyl N-[({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}-methyl)]carbamate;

TRANS-N2-(4-(1-morpholinylcarbonyl)]cyclohexyl-8-methoxy-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine hydrochloride;

3-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)-amino]cyclohexyl}methyl)- 1,3-oxazolin-2He;

2-chloroethyl-N-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}methyl)-carbamate;

3-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)amino]cyclohexyl}methyl)-1,3-oxazolin-2He;

N-({4-[(9-fluoro-5,6-dihyd the on-4H-benzo[6,7]cyclohepta-[D][1,3]thiazol-2-yl)amino]cyclohexyl}methyl)-2-methoxyacetate;

N1-({4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]-cyclohepta-D][1,3]thiazol-2-yl) amino]cyclohexyl}methyl)ndimethylacetamide;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(N-propylbromide)methyl)cyclohex-Salamina-3-thia-benzo[e]azulene;

TRANS-1-Aza-9-fluoro-4,5-dihydro-2-(4-(N-isopropylamino)methyl)cyclohexylamino-3-thia-benzo[e]azulene;

N1-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)methyl]cyclohexyl}-2-methoxyacetate;

benzyl-N-(4-{[(aminocarbonyl)amino]methyl}cyclohexyl)-carbamate;

benzyl-N-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]-thiazol-2-yl-amino)methyl]cyclohexyl}carbamate;

N2-[(4-aminocyclohexane)]methyl]-4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3] thiazole-2-amine;

N-{[4-(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)cyclo-hexyl]methyl}-N-propylparaben;

N1-{[[4-(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)cyclo-hexyl]methyl}propanamide;

N2-{4-[(propylamino)]methyl]cyclohexyl}-4,5-dihydrobenzo-[2,3]oxepin-[4,5-d][1,3]thiazole-2-amine;

N-[{[4-(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)cyclo-hexyl]methyl}-N-propylparaben;

N-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][[1,3]thiazole-2-ylamino)methyl]cyclohexyl}-N-(2-methoxyethyl)formamide;

N2-({4-[(2-methoxyethyl)amino]cyclohexyl}methyl)-4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-amine;

N-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)methyl]cyclohexyl}-N-(2-methoxyethyl)formamide;

TRANS-1-Aza-2-(4-(n-(ethyl)formamide)cycle is hexyl)methyl-amino-4,5-dihydro-6-oxa-3-thia-benzo[e]azulene;

TRANS-2-(4-acetamido)cyclohexylethylamine-1-Aza-4,5-dihydro-6-oxa-3 - thia-benzo[e]azulene;

benzyl-N-[4-{[(benzoylamine)carbothioic]amino}methyl)-cyclohexyl]carbamate;

benzyl-N-(4-{[(aminocarbonyl)amino]methyl}cyclohexyl)carbamate;

benzyl-N-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]-thiazol-2-yl-amino)methyl]cyclohexyl} carbamate;

N2-[(4-aminocyclohexane)methyl]-4,5-dihydrobenzo[2,3]-oxepin-[4,5-d][1,3]thiazole-2-amine;

N1-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]-thiazole-2-ylamino)methyl]cyclohexyl}ndimethylacetamide;

N2-[4-(ethylamino)cyclohexyl]methyl}-4,5-dihydrobenzo-[2,3]oxepin[4,5-d][1,3]thiazole-2-amine;

N-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)methyl]cyclohexyl}-N-ethylformate;

N-(4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)methyl]cyclohexyl}-N-propylparaben;

N2-{[4-(propylamino)cyclohexyl]methyl}-4,5-dihydrobenzo-[2,3]oxepin[4,5-d][1,3]thiazole-2-amine;

N-{4-[(4,5-dihydrobenzo[2,3]oxepin[4,5-d][1,3]thiazole-2-ylamino)methyl]cyclohexyl}-N-propylparaben;

N1-{4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl)amino]benzyl}-2-methoxyacetate;

N-{4-[(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-yl) amino]benzyl}methanesulfonamide;

N2-[4-(aminomethyl)phenyl]-9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazole-2-amine.

Reference: U.S. Patent No. 6225330

Bicyclic compounds of the Y receptor antagonists, such as:

2-(5-diethylamino is phenylamino)pentylamine-4-(2-pyridyl)thiazole hydrochloride

4-(2-pyridyl)-2-(5-(2-thienyl)sulfonylamino)aminothiazole hydrochloride

2-(5-(2-forfinal)sulfonylamino)pentylamine-4-(2-pyridyl)thiazole hydrochloride

2-(5-(4-methoxyphenyl)sulfonylamino)pentylamine-4-(2-pyridyl)thiazole hydrochloride

2-(5-(3,5-dimethylisoxazol-4-yl)sulfonylamino)pentylamine-4-(2-pyridyl)thiazole hydrochloride

2-(5-(3,4-differenl)sulfonylamino)pentylamine-4-(2-pyridyl)thiazole hydrochloride

2-(5-(2-methoxy-5-were)sulfonylamino)pentylamine-4-(2-pyridyl)thiazole hydrochloride

2-(5-(benzylmethylamine)pentylamine-4-(2-pyridyl)thiazole hydrochloride

2-(5-(ethylsulfonyl)pentyl)amino-4-(2-pyridyl)thiazole hydrochloride

2-(5-(triftormetilfullerenov)pentyl)amino-4-(2-pyridyl)thiazole hydrochloride

2-(5-(aminosulfonyl)pentyl)amino-4-(2-pyridyl)thiazole hydrochloride

2-(5-(2-forfinal)sulfonylamino)pentylamine-4-(3-pyridyl)thiazole hydrochloride

2-(5-(3,5-dimethylisoxazol-4-yl)sulfonylamino)pentylamine-4-(3-pyridyl)thiazole hydrochloride

2-(5-(2-methoxy-5-methyl)phenylcarbonylamino)pentylamine-4-(3-pyridyl)thiazole hydrochloride

2-(5-(2-fluoro)phenylcarbonylamino)pentylamine-4-(4-pyridyl)thiazole hydrochloride

2-(5-(3,5-dimethylisoxazol-4-yl)sulfonylamino)pentylamine-4-(4-pyridyl)thiazole hydrochloride

2-(5-(2-methoxy-5-methyl)phenylcarbonylamino)pentylamine-4-(4-pyridyl)thiazole hydrochloride

N-5-[(4-benzo[b]thiophene-2-yl-1,3-thiazol-2-yl)amino]-pentyl}-2-methoxy-5-methyl-1-benzosulfimide

N1-(5-{[4-(5-[ENT-3-methylbenzo[b]thiophene-2-yl)-1,3-thiazol-2-yl]amino}of pentyl)-2-methoxy-5-methyl-1-benzene-sulfonamide

N1-(4-{[4-(5-phenyl-3-isoxazolyl)-1,3-thiazol-2-yl)amino}-pentyl)-2-methoxy-5-methyl-1-benzosulfimide

N1-(5-{[4-(3-thienyl)-1,3-thiazol-2-yl]amino}of pentyl)-2-methoxy-5-methyl-1-benzosulfimide

N1-[5-({4-[1-(phenylsulfonyl)-1H-3-pyrrolyl-1,3-thiazol-2-yl}amino)pentyl]-2-methoxy-5-methyl-1-benzosulfimide

TRANS-8-[(4-{[4-(3-Phenyl-5-isoxazolyl)-1,3-thiazol-2-yl]amino}cyclo-hexyl)methyl]-8-chinaincorporated

N,N-dimethyl-N'-(5-{[4-(3-thienyl)-1,3-thiazol-2-yl]amino}of pentyl)sulphonamide

TRANS-2-(4-(2-methoxy-5-were)sulfonylamino)cyclohexylmethyl-amino-4-(2-pyridyl)thiazol the dihydrochloride

TRANS-2-(4-(2-forfinal)sulfonylamino)cyclohexylmethyl-amino-4-(2-pyridyl)thiazol the dihydrochloride

TRANS-2-(4-(3,5-dimethyl-4-isoxazolyl)sulfonylamino)cyclohexylmethyl-amino-4-(2-pyridyl)thiazol the dihydrochloride

TRANS-2-(4-(2-forfinal)sulfonylamino)cyclohexylmethyl-amino-4-(3-pyridyl)thiazol the dihydrochloride

TRANS-2-(4-(2-methoxy-5-were)sulfonylamino)cyclohexylmethyl-amino-4-(4-pyridyl)thiazol the dihydrochloride

N1-(5-[4-(1,3-thiazol-2-yl)-1,3-thiazol-2-yl]aminopentyl)-2-methoxy-5-methyl-1-benzosulfimide

TRANS-N1-[(4-[4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]aminocyclo-hexyl)methyl]-2-methoxy-5-methyl-1-benzosulfimide

TRANS-N,N-dimethyl-N'-[(4-[4-(-1,3-thiazol-2-is)-1,3-thiazol-2-yl]amino-cyclohexyl)methyl]sulphonamide

N,N-dimethyl-N'-(5-{[4-(2-thienyl)-1,3-thiazol-2-yl]amino}of pentyl)sulphonamide

N1-(5-{[4-(2-thienyl)-1,3-thiazol-2-yl]amino}of pentyl)-2-methoxy-5-methyl-1-benzosulfimide

N1-(5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]aminopentyl)-2-methoxy-5-methyl-1-benzosulfimide

N1-(5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]aminopentyl)-4-fluoro-1-benzosulfimide

N1-(5-[4-(1,3-thiazol-2-yl)-1,3-thiazol-2-yl]aminopentyl)-4-fluoro-1-benzene - sulfonamide

N'-(5-[4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]aminopentyl)-N,N-dimethylsulfone

TRANS-N1-[(4-[4-(2,6-dimethyl-1,3-thiazol-4-yl])-1,3-thiazol-2-yl]amino-cyclohexyl)methyl]-4-fluoro-1-benzene-sulfonamide

TRANS-N'-[(4-[4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]amino-cyclohexyl)methyl]-N,N-dimethylsulfone]

TRANS-N'-[4-([5-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]amino-methyl)cyclohexyl]methyl-N,N-dimethyl-sulphonamide

TRANS-N4-[4-([4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]amino-methyl)cyclohexyl]methyl-4-morpholine-sulfonamide

TRANS-N-[4-([4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]amino-methyl)cyclohexyl]-N-(2-methoxyethyl)formamide

TRANS-N-[4-([4-(2,5-dimethyl-1,3-thiazol-4-yl)-1,3-thiazol-2-yl]amino-methyl)cyclohexyl]-N-Isopropylamine

Reference: see U.S. Patent No. 6218408

N-aralkylamines receptor antagonist Y, such as:

rac-CIS-1-(phenylmethyl)-6-methoxy-N-(2-(3,4-acid)ethyl)-1,2,3,4-tetrahydro-2-naphthalenamine;

rac-CIS-1-(penile who yl)-6-methoxy-N-(2-(3-indolyl)ethyl)-1,2,3,4-Tetra-hydro-2-naphthalenamine hemifumarate;

rac-CIS-1-(phenylmethyl)-N-(4-performer)-1,2,3,4-tetrahydro-2-naphtha-linemen monohydrobromide;

rac-CIS-1-(phenylmethyl)-N-(2-methoxyphenylacetyl)-1,2,3,4-tetrahydro-2 - naphthalenamine;

rac-CIS-1-(phenylmethyl)-N-(2-methoxyphenylacetyl)-1,2,3,4-tetrahydro-2-naphthalenamine monohydrobromide;

rac-CIS-1-(4-performer)-N-(2-methoxyphenylacetyl)-1,2,3,4-tetrahydro-2-naphthalenamine monohydrobromide;

rac-TRANS-1-(4-performer)-N-(2-methoxyphenylacetyl)-1,2,3,4-tetrahydro-2-naphthalenamine monoacetate;

rac-CIS-1-(phenylmethyl)-N-(4-performer)-1,2,3,4-tetrahydro-2-naphtha-linemen monohydrobromide;

rac-CIS-1-(phenylmethyl)-7-methoxy-N-(2-methoxyphenylacetyl)-1,2,3,4-Tetra-hydro-2-naphthalenamine monohydrobromide;

rac-TRANS-1-(4-performer)-N-(2-(3-indolyl)ethyl)-1,2,3,4-tetrahydro-2-naphthalenamine monoacetate;

rac-CIS-1-(phenylmethyl)-N-(2-methoxyphenyl-2-oxoethyl)-1,2,3,4-tetrahydro-2-naphthalenamine monohydrobromide;

rac-CIS-1-(phenylmethyl)-7-methoxy-N-(2-(3-indolyl)ethyl)-1,2,3,4-tetrahydro-2-naphthalenamine 0.8 fumarate 0.8 methanol 0.2 hydrate;

rac-TRANS-1-(phenylmethyl)-7-methoxy-N-(2(3-indolyl)ethyl)-1,2,3,4-Tetra-hydro-2-naphthalenamine monoacetate;

rac-CIS-1-(2-naphthylmethyl)-N-(2-(3-indolyl)ethyl)-1,2,3,4-tetrahydro-2-naphthalenamine hemifumarate methanol;

rac-TRANS-1-(2-naphthylmethyl)-N-(2-(3-indolyl)ethyl)-1,2,3,4-tetrahydro-2-naphthalenamine monoacetate;

rac-CIS-1-(2-naphthylmethyl)-N-(2-methoxyphenylacetyl)-1,2,3,4-tetrahed what about the-2-naphthalenamine monohydrobromide;

rac-CIS-1-(phenylmethyl)-N-(2-methoxyphenyl-2-oxoethyl)-1,2,3,4-tetrahed-ro-2-naphthalenamine;

rac-CIS-1-(4-performer)-N-(3-phenylpropyl)-1,2,3,4-tetrahydro-2-naphthalenamine monohydrobromide;

rac-CIS-1-(3-pyridylmethyl)-N-(2-(3,4-acid)ethyl-1,2,3,4-Tetra-hydro-2-naphthalenamine monohydrobromide.

Reference: see U.S. Patent No. 6201025

Amide derived receptor antagonist Y:

Reference: see U.S. Patent No. 6048900

N-substituted aminotetraline the Y receptor antagonists, such as:

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-methoxy-1-(phenylmethyl)-2-naphthalenyl]amino]methyl]4-cyclohexyl]methyl]2-naphthalenesulfonate;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-methoxy-1-(phenylmethyl)-2-naphthalenyl]amino]-5-pentyl]2-naphthalenesulfonate;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-methoxy-1-(3 - pyridinyl-methyl)-2-naphthalenyl]amino]methyl]-4-cyclohexyl]methyl]2-naphthalenesulfonate;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-fluoro-1-(phenylmethyl)-2-naphthalenyl]amino]methyl]-4-cyclohexyl]methyl]2-forbindelsesfaneblad;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-fluoro-1-phenyl-2-naphthalenyl]amino]methyl]-4-cyclohexyl]methyl]2-naphthalenesulfonate;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-methoxy-1-(1-propen-3-yl)-2-naphthalenyl]amino]methyl]4-cyclohexyl]methyl]benzosulfimide;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-methoxy-1-(3-hydroxy-propyl)-2-naphthalenyl]amino]methyl]-4-cycle is hexyl]methyl]benzosulfimide;

rac-[1α,2α(TRANS)]-N-[[[[[1,2,3,4-tetrahydro-6-methoxy-1-(n-propyl)-2-naphthalenyl]amino]methyl]-4-cyclohexyl]methyl]benzosulfimide.

Reference: see U.S. Patent No. 6140354

4-phenyl-1,4-dihydropyrimidine derived receptor antagonist Y:

Reference: see U.S. Patent No. 5889016

Piperidine derivative of dihydropyridine receptor antagonist Y:

Dimethyl ester

4-dihydro-[3-[[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5 - pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-hydroxy-4-(3-methoxyphenyl)piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(2-methoxyphenyl)piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-(4-phenylpiperazin-1-yl) propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-(4-hydroxy-4-phenylpiperidine-1-yl)propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-2,6-dimethyl-4-[3-[[[[3-[4-[3-(2-propenyloxy)phenyl]-1-piperidinyl]propyl]amino]carbonyl]amino]phenyl] - for 3,5-pyridinedicarboxylic acids;

D. the methyl ester

1,4-dihydro-4-[3-[[[[3-[4-cyano-4-phenylpiperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(3-hydroxyphenyl)piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-naphthalene-1-reparacin-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

4-[3-[[[[3-[4-(1,1'-biphenyl-3-yl)piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(phenylmethyl)-piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

4-[3-[[[[3-(4-cyclohexyl-1-piperidinyl)propyl]amino]carbonyl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-hydroxy-4-(2-phenoxyphenyl)-1-piperidinyl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Utilmately ester

1,4-dihydro-4-[3-[[[[3-(4-phenyl-1-piperidinyl)propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Utilmately ester

1,4-dihydro-4-[3-[[[[3-[(4-phenylmethyl)-1-Piperi inyl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Utilmately ester

1,4-dihydro-4-[3-[[[3-[[4-hydroxy-4-(2-methoxyphenyl)-piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Utilmately ester

1,4-dihydro-4-[3-[[[[3-[4-hydroxy-4-(3-methoxyphenyl)-piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-2,6-dimethyl-4-[3-[[[[3-[4-[3-(2-propoxy)phenyl]-1-piperid-Neil]-propyl]amino]carbonyl]amino]phenyl] - for 3,5-pyridinedicarboxylic acids;

Dimethyl ester of 1,4-dihydro-4-[3-[[[[2-[4-[(3-methoxyphenyl)-1-]piperidinyl]ethyl]amino] carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

1,4-dihydro-4-[3-[[[[4-[4-(3-methoxyphenyl)-1 - piperidinyl]butyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

1,4-Dihydro-4-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]methyl-amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

4-dihydro-4-[3-[[[[3-[1,2,3,6-tetrahydro-4-(3-methoxyphenyl)pyridine-1-yl] propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-(1,2,3,6-tetrahydro-4-phenylpyridine-1-]yl)propyl]amino]carbonyl]and the eno]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[1,2,3,6-tetrahydro-4-(3-hydroxyphenyl)pyridine]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-1,2,3,6-tetrahydro-4-(1-naphthalenyl)-1-a]pyridinyl] propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[3-(4-phenylpiperazin-1-yl)-1-oxo-1-propyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[4-(4-phenylpiperazin-1-yl)-1-oxo-1-butyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[5-(4-phenylpiperazin-1-yl)-1-oxo-1-pentyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[6-(4-phenylpiperazin-1-yl)-1-oxo-1-hexyl]amino]] phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[5-(4-hydroxy-4-phenylpiperidine-1-yl)-1-oxo-1-]pentyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[5-(4-cyano-4-phenylpiperidine-1-yl)-1-oxo-1-pentyl]]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[4-[[4-(3-methoxyphenyl)-1-piperidinyl]butyl] carbonyl]amino]enyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]oxy]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, hydrochloride;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(3-methoxyphenyl)-piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(2-methoxyphenyl)piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[4-(3-hydroxyphenyl)piperidine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[[4-naphthaleneboronic-1-]yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid,

Dimethyl ester

4-[3-[[[[3-(4-cyclohexyl-1-piperidinyl) propyl]amino]carbonyl]amino]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[[3-[1,2,3,6-tetrahydro-4-(3-methoxyphenyl)pyridine-1-yl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acids;

Dimethyl ester

1,4-dihydro-4-[3-[[[3-[1,2,3,6-tetrahydro-4-(1-naphthalenyl)pyridine-1-yl] propyl]amino]carbonyl]amino]phenyl-2,6-dimethyl-3,5-pyridinedicarboxylic acid.

As described in this context, it has been found that the introduction of human PYY reduces appetite. With limited human physiological levels corresponding to the levels of postprandial PYY_3-36significantly reduces the appetite and reduces the absorption of food by one-third within 12 hours and one-third even within 24 hours. The effect and duration of effect are unexpected and unpredictable, because they last for many hours after removal of the hormone from the circulation. Effects, which are formed using physiological levels of the peptide are strong indications that the effect of PYY in vivo is in the regulation of feeding behavior.

As described in this context, the peripheral introduction PYY_3-36causes of rats increased immunoreactivity of c-fos in the arcuate nucleus of the hypothalamus and decrease in mRNA level of the hypothalamic neuropeptide Y (NPY). In addition, electrophysiological studies have demonstrated that PYY_3-36inhibits nerve endings containing NPY and activates thus neurons O.G. ROMs, which are known to have an inhibiting synaptic inputs NPY.

Regardless of theory, these results demonstrate that intestinal hormone PYY_3-36may act via receptor Y2 n is isopeptide Y. This assumption supports the observation that with the introduction of PYY_3-36mice that are missing the receptor Y2 neuropeptide Y (mouse whose embossed gene Y2R), no suppression of food intake is not noted. Introduction PYY_3-36the offspring of wild-type mice data with no Y2R gives the full effect of the suppression of food intake.

Thus, this paper describes a new route connecting the gut and the brain, which suppresses food after feeding. Regardless of theory, the natural path includes the release of PYY from the gut and its transformation into PYY_3-36which acts as an agonist of the receptor Y2 neuropeptide Y receptor Y2 NPY) in the brain. The Y2 receptor NPY acts as an inhibitory presynaptic receptor that reduces the release of neuropeptide Y, which is the most powerful stimulator of food, and also acts on anorectic melanocortin system. As a result, the activity of the receptor Y2 NPY suppresses appetite and reduce food intake. The effect of PYY_3-36can be done in the arcuate nucleus of the hypothalamus, but can also be employed on other areas.

The results show that intestinal hormone PYY_3-36which circulates in the blood, suppresses appetite in physiological concentrations, and that the inhibitory effect is observed even after several hours after taken the help of the hormone from the blood. This effect is shown in all studied species, i.e. mice, rats and humans. Apparently circulating in the blood of the intestinal hormone acts through the cycle of the hypothalamus. The decrease in the level of mRNA, required for the synthesis appetitively hormones brain, in particular mRNA hypothalamic NPY may be a possible mechanism of long-term action PYY_3-36.

Description of the invention is illustrated by the following non-limiting Examples.

EXAMPLES

Example 1

Materials and methods

Getting mice POMC-EGFP: EGFP cassette contains its own consensus site of translation initiation Kozak together with the signal of the SV40 polyadenylation, which are located along the broadcast below EGFP coding sequences, and send the appropriate processing of the 3'end of the EGFP mRNA. The EGFP cassette being introduced by standard techniques in the 5'-noncoding segment of exon 2 of the mouse genomic clone Rota, which contains 5'- and 3'-flanking sequences size 13 TPN and 2 TPN, respectively (see Young et al., J. Neurosci. 18:6631-40, (1998)). The transgene microinjection injected into the pronuclei of embryos of mice C57BL/6J at the stage of a single cell (Jackson Laboratories), as described in Young et al. (see J. Neurosci. 18:6631-40, (1998)). Get the founder of the line and cross it with wild type C57BL/6J order to obtain homozygote m is N1 necks. In addition, also get N2 and the subsequent generation of mice homozygous for a given transgene. Mice are fertile and have normal growth and development.

Immunofluorescence and colocalization GFP: Mice under anesthesia transcardial pour in 4% paraformaldehyde and vibratome prepare free-floating brain slices. Slices treated to obtain immunofluorescence assay and determine colocalization GFP fluorescence using standard techniques. Use the following primary anticigarette and its dilution: rabbit against β-endorphin 1:2500 rpm./vol.; rabbit against NPY, 1:25000.about. (Alanex Corp.); rabbit against ACTH, 1:2000 rpm./about. and mouse against TN, 1:1000.about. (Incstar). After washing the sections incubated with 10 mg/ml biotinylated horse IgG against mouse, rabbit (Vector Laboratories) followed by treatment Cy-3-conjugated-streptavidin, 1:500.about. (Jackson Immunoresearch Laboratories). Micrograph do with Zeiss Axioscop when using filter sets FITC and RITC (Chroma Technology Corp.).

Electrophysiology (Example 2): Coronal slices of a thickness of 200 μm made from ARC male mice POMC-EGFP four weeks of age. The support sections in a medium containing (in mm) NaCl, 126; KCl 2,5; MgCl₂1,2; CaCl₂.2H₂O 2,4; NaH₂PO₄.H₂O 1, 2; NaHCO₃21,4; glucose of 11.1 (Krebs), at 35°C and saturated with 95% O₂and 5% CO₂in accordance with the s 1 hour (h) to record results. Registration is done in the environment Krebs at 35°C. the Slices visualize using Axioskop FS2 (Zeiss) using standard infrared optics and epifluorescence through the FITC filter set (see Figure 1C). Registration data on whole cells do with fluorescent neurons using an amplifier Axopatch 1D (Axon Instruments) and Clampex7 (Axon Instruments). Membrane resting potentials determined using the Protocol detection events in the PowerLab system (AD Instruments, Mountain View, CA) for averaging the received registration device extended recordings of membrane potential. Medicinal substances contribute to the capacity at the specified time points. Membrane resting potential remains stable for hours in cells treated only environment Krebs. Curves I-V for currents Met-Enk determined using a stepwise Protocol; supported the potential of -60 mV, sequentially pulse (40 MS) from -120 to -50 mV, the cells are returned to -60 mV for 2 s between power surges). The Protocol is repeated after adding Met Enk. The mains voltage is the difference between the two curves I-V. This Protocol is repeated in the environment Krebs containing 6.5 mm K⁺. Curves I-V to determine the postsynaptic latinoware current determined in a similar way when using a slow ramp voltage (5 mV/s from -100 to -20 mV) to the within 10 minutes after injection of leptin (100 nm). GABAergic IPSCs recorded using the internal solution for electrodes CsCl containing (in mm): CsCl 140; Hepes 10; MgCl₂5; Bapta 1; (Mg)-ATP 5; Na-GTP 0.3 to. In untreated slices see both as mini IPSCs and IPSCs large amplitude (obviously, multisynaptic). TTX (1 μm) removes large IPSCs. Data obtained before and after addition of the drug substance for the time points indicated in the Figures, supporting the potential of -50 mV and fluctuations 2 for every 4 C. Minigostinitsa currents analyzed using Axograph 4 (Axon Instruments). IPSCs and excitatory postsynaptic currents (EPSCS) are divided by the constant fading, the introduction of additional picrotoxin (100 μm) blocks all IPSCs. Neurons O.G. ROMs get low signal EPSC, and none of the methods in this context effects do not modulate the frequency.

Immunoablative for light and electron microscopy: a Double immunocytochemical reaction for NPY and O.G. ROMs using diaminobenzidine of Chromogens (DAB) different colors are conducted on fixed hypothalamus mice according to published protocols (see Horvath et al., Neuroscience, 51,391-9, (1992)). Electron microscopy for immunostaining for β-endorphin before concluding material used set of ABC Elite (Vector Laboratories) and carrying out the reaction of DAB with the subsequent conclusion of the mA is Arial. After the conclusion of GABA and NPY have been labelled rabbit anti-GABA in the ratio of 1:1000.about. and conjugated with gold (10 nm) goat IgG against rabbit or sheep against NPY and conjugated with gold (25 nm) goat IgG against sheep. Finally, sections contrasting paint saturated uranylacetate (10 min) and lead citrate (20-30 C) and examined using an electron microscope Philips CM-10.

Animals: Male Wistar rats (weighing 200-250 g), aged 7-8 weeks (Charles River Laboratories, United Kingdom) contain at controlled temperature (21-23°C) and lighting conditions (light from 07:00 to 19:00) with free access to water and food (RM1 diet; SDS Ltd., Witham, United Kingdom) unless otherwise stated. Kanalirovanie and injection arched and paraventrikulyarnoe engine is carried out, as described previously (see Glaum et al., Mol. Pharmacol., 50:230-5, (1996); Lee et al., J. Physiol. (Lond) 515:439-52, (1999); Shiraishi et al., Nutrition, 15:576-9, (1999)). The correct position of the cannula inside the nucleus confirmed histologically at the end of each study period (see article Glaum et al., Mol. Pharmacol., 50:230-5, (1996); Lee et al., J. Physiol. (Lond), 515:439-52, (1999); Shiraishi et al., Nutrition, 15:576-9, (1999)). All procedures with animals were approved by the Chief of Department on work with animals in the UK (British Home Office Animals (Law on scientific procedures (Scientific Procedures Act, 1986. All studies on the hungry animals that are associated with injections, spend the early light phase (08:00-09:00). All injections in studies of the food during the dark phase carried out directly before turning off the light.

Male mice Pomc-EGFP explore at 5-6 weeks of age and receive, as described above. Mice, Y2r-null, the benefits of using recombination mediated by Cre-lox P, which leads to deletion of the germ line of the whole coding part of the Y2 receptor. All mice Y2r-null support on a mixed background of C57/B16-129SvJ. Male mice aged 8-12 weeks and weight 2-30 g contain at controlled temperature (21-23°C) and lighting (lights on from 06:00 to 18:00) with free access to feed and water (Gordon's Speciality Stock feeds), unless otherwise specified. All studies conducted during the early light phase (07:00-08:00).

Intraperitoneal injections: Rats adapt to intraperitoneal injection, making intraperitoneal injection of 0.5 ml of physiological solution for two days prior to the survey. In all studies, animals do intraperitoneal injection or PYY_3-36or saline in a volume of 500 ál (for rats) or 100 µg (for mice).

Electrophysiology: the Records of the registering devices of the patch-clamp (fixed potential) in the intact cells are neurons O.G. ROMs in coronal sections of the hypothalamus thickness of 180 μm mice Pomc-EGFP as described previously (see Cowley et al., Nature, 411:480-484, (2001)). Recording recording devices, SV is freely attached to the cells, make using extracellular buffer in the electrode solution and maintaining the insulating resistance between 3 and 5 mW for recording. The number of pulses determined using protocols minianalysis (MiniAnaLysis, Jaejin Software, NJ). Controls in the form of media used in this system, pre-check in terms of electrophysiological actions of neuropeptides (see Cowley et al., Nature, 411:480-484, (2001)). Data analyzed by ANOVA, posthoc comparison Neuman-Keuls and using the relative rank Wilcoxon criterion.

The hypothalamic explants: Male Wistar rats killed by decapitate and immediately the entire remote brain fix ventral surface facing up and placed in a vibrating microtome (Biorad, Microfield Scientific Ltd., Dartmouth, UK). Cut to a thickness of 1.7 mm is obtained from the base of the brain so that it includes VAT and ARC and immediately transferred into 1 ml of artificial CSF (cerebral spinal fluid) (aCSF) (see Kim et al., J. C1in. Invest., 105:1005-11, (2000)), which balance 95% O₂and 5% CO₂and maintain at 37°C. After the initial 2-hour period of equilibration with aCSF replaced every 60 minutes, samples of the hypothalamus incubated for 45 minutes in 600 µl aCSF (base period) before processing Y2A (50 nm) in 600 μl of aCSF. Finally, to check the viability of the tissue by processing within 45 minutes 56 is M Kl; isotonicity support the replacement of K⁺on the Na⁺. At the end of each period aCSF removed and frozen at -20°C prior to radioimmunoassay for NPY and aMSH.

Expression of C-fos: the Expression of C-fos was measured in Mature Wistar rats and mice Pomc-EGFP 2 hours after intraperitoneal administration of saline or PYY_3-36(5 μg/100 g) using standard immunohistochemical techniques (see Hoffman et al., Front. Neuroendocrinol., 14:173-213, (1993)). Data are obtained in groups of 3 rats and 5 mice each. For mice Pomc-EGFP each animal count 5 anatomically close sections of the arcuate nucleus (see monograph Franklin et al., Head mouse brain in stereotaxic coordinates (The Mouse Brain in Stereotaxic Coordinates), Academic Press, San Diego, (1997)) and make images using a confocal microscope Leica TSC (see Grove et al., Neuroscience, 100:731-40, (2000)).

Analysis of the RNase protection (RPA)Total RNA extracted from hypothalamus (Trizol, Gibco). RPA carried out (set RPAIII, Ambion) using 5 μg of RNA and probes that are specific against NPY, aMSH and β-actin (internal standard). For each neuropeptide calculate the ratio of the optical density of the bands neuropeptide mRNA with an optical density of β-actin. Levels of mRNA expression of neuropeptide expressed relative to the control in the form of a saline solution (mean ± s.e.m., n=4/group). When statisticheskoi analysis using ANOVA analysis with post hoc Bonferroni.

Analyses of plasma: For measuring human leptin use a commercially available radioimmunoassays (RIA) (Unco Research, USA). The levels of other hormones in the plasma was measured using the RIA (see Tarling et al., Intensive Care Med., 23:256-260, (1997)). Glucose concentration was measured using the YSI analyzer 2300STAT (Yellow Springs Instruments Inc., Ohio, USA). The levels of paracetamol in plasma was measured using an enzymatic colorimetric analysis (analyzer Olympus AU600 analyzer).

Human studies: PYY_3-36acquire the company Bachem (California, USA). Test using lysate of amoebocytes Limulus on pyrogens is negative, and the peptide with the introduction of sterile crops. Ethical permit is obtained from the local ethics Committee of research (Local Research Ethics Committee (Registration project registration) 2001/6094) and conduct the study in accordance with the principles of the Declaration of Helsinki. The actors give their written consent on the basis of the received information.

Each subject is study twice with an interval of at least 1 week between each of the studies. Voluntary study participants fill out a food diary for three days prior to each infusion and the subsequent 24 hours. All subjects fast and drink only water from 20:00 h in the evening prior to each study. Actors arrive in 0:30 each day research they introduce the cannula and allow to rest for 30 minutes before the start of the study Protocol. Blood samples are taken every 30 minutes in heparinized tubes containing 5000 units of the inhibitor of kallikrein (0.2 ml) Aprotinin (Bayer), and centrifuged. The plasma is separated and then stored at -70°C until analysis. Subjects injected with either saline or 0,8 Polk^-1Min^-1PYY_3-36within 90 minutes (total infusion is approximately 72 pmol) in a double-blind randomized mixed format.

Two hours after injection the subjects offered free choice of snacks in abundance (see Edwards et al., Am. J. Physiol. Endocrinol. Metab., 281:E155-E166, (2001)), so that you can satisfy all appetites. Food and water are weighed before and after food intake and calculate the caloric intake. Assessment of appetite do using a 100 mm visual analog accounting system (VAS) with lyrics expressing the most positive and negative evaluation, attached to each end (see Raben et al., Br. J. Nutr., 73:517-30, (1995). The VAS is used to assess hunger, satiety, fullness, prospective food consumption and nausea. The calorie intake after administration of saline and PYY_3-36compared using paired student's criterion. Curves of response to receiving PI and compared using ANOVA using repeated paired measurements taking into account such factors as time and treatment option.

Measurement of energy expenditure: To determine the effect of PYY on energy costs using the OXYMAX system in rodents after the injection of PYY in the treatment group. This system is also used on rodents after injection of saline (control group). The equipment measures the consumption of O₂and education CO₂while the efficiency with which the body forms a CO₂of O₂gives reliable, the efficiency of use of calories or metabolism. A similar system is used on people who are voluntary participants in the experiment.

Example 2

Neural network in the arcuate nucleus

Get a line of transgenic mice expressing the protein of green fluorescence (EGFP Clontech) under the transcriptional control of the genomic sequences of mouse Pomc, which include the area located between -13 TPN and -2 TPN required for the accurate expression in neurons (see Young et al., J. Neurosci., 18:6631-40, (1998)) (see Figure 1a). Bright green fluorescence is observed in two regions of the CNS, where it is formed O.G. ROMs - ARC and the nucleus of the solitary path. Under UV light (450-480 nm) excitation of neurons O.G. ROMs clearly different from the surrounding effluorescence neurons (see Figure 1b), visualized using infrared optics. Double immunofluorescence shows gt; 99% of cell colocalization peptides EGFP and O.G. ROMs ARC (see Figure 1c). There is a close overlap endings, painted tyrosinekinase (TN) and NPY on neurons O.G. ROMs expressing EGFP, but there is no evidence of colocalization immunoreactivity TN or NPY with EGFP. The total number of fluorescent cells in coronal sections of the hypothalamus is 3148+62 (mean ± SEM, N=3) neuronal POMC-EGFP, distributed in the whole ARC (see monograph Franklin et al., Head mouse brain in stereotaxic coordinates (The Mouse Brain in Stereotaxic Coordinates), Academic Press, San Diego, (1997)) (see Figure 1d). Neurons O.G. ROMs mouse are located in the ARC as the medial and ventral in contrast to the predominantly lateral position in the ARC of rats.

The neuronal POMC-EGFP in slices of hypothalamus have membrane resting potential of -40 to -45 mV and demonstrate frequent spontaneous action potentials. Non-selective opioid agonist met-enkephalin (Met-Enk, concentration 30 µm; Sigma) causes a rapid (35-40 C) reversible hyperpolarization (10-20 mV) membrane potential of cells O.G. ROMs (N=10) and prevents the spontaneous generation of action potential (see Figure 2A). In normal (2.5 mm K⁺) Krebs buffer reversible potential incoming rectifying opioid current is approximately -90 mV, whereas 6.5 mm K⁺the Krebs buffer reversible potential is shifted to approximately -60 mV (n=3, see Figure 2b) Antagonist OLD mu-opioid receptor (MOP-R) (at a concentration of 1 μm; Phoenix Pharmaceuticals) completely suppresses the current induced Met-Enk in the cells O.G. ROMs (n=3, see Figure 2C). These characteristics indicate that opioid current due to the activation of MOP-R and increased conductivity of ions through internally regulated potassium channels associated with G-protein (GIRK) (Kelly et al., Neuroendocrinology, 52:268-75, (1990)).

Response to opioids in EGFP-labeled neurons O.G. ROMs, similar reactions in cells O.G. ROMs Guinea pigs (see Kelly et al., Neuroendocrinology, 52:268-75, (1990)) or mice (see Slugg et al., Neuroendocrinology, 72:208-17, (2000)), identified using immunohistochemical reactions after registration, suggest that the expression of the EGFP transgene does not violate neither the expression of the receptor or the binding of secondary vectors in neurons O.G. ROMs.

Next examine the direct effect of leptin on the identified cells O.G. ROMs in drugs slices. Leptin (in a concentration of 0.1-100 nm) causes depolarization 72 of 77 cells O.G. ROMs on 3-30 mV (see Figure 3a; the average depolarization ± SEM when exposed to leptin at a concentration of 100 nm=9,7±1.2 mV, n=45) for 2-10 minutes, depending on the concentration (see Figure 3b). In depolarization involves two components and none of them recovered completely within 40 minutes. First, depolarization due to a small inward current, which is reversible, if priblizitel is but -20 mV (see Figure 3C), suggesting participation in the process of nonspecific cation channel (see Powis et al., Am. J. Physiol., 274:R1468-72, (1998)). Secondly, the effects of leptin reduces GABAergic signal cells O.G. ROMs. GABAergic brake postsynaptic currents (IPSCs) are observed in cells O.G. ROMs and leptin (at a concentration of 100 nm) reduces the frequency of 25% (see Figure 3d) in 5 out of 15 cells. This suggests that it acts at presynaptic, reducing the release of GABA (leptin no effect on IPSCs in 10 of the 15 neurons O.G. ROMs). The effect on the frequency of IPSC similar effect on membrane potential. Thus, he not only causes the depolarization of neurons O.G. ROMs, but also acts on GABAergic nerve endings, reducing the release of GABA on neurons O.G. ROMs that allows them to take a more depolarized the resting potential. Existing depolarization of cells O.G. ROMs leptin is specific, because leptin has no effect on 5 of the 13 investigated neighboring afluorescent cells (see Figure 3E), whereas it causes hyperpolarization 5 (see Figure 3f) and depolarization 3 other neurons in the not-O.G. ROMs ARC. Electrophysiological effects of leptin described in this context correspond to the biological activity of leptin; leptin quickly causes the output o-MSH from rat hypothalamus (see Kim et al., J. Clin. Invest., 105:1005-11, (2000)), mainly through activation of neurons O.G. ROMs.

Previous reports of hyperpolarization of neurons by leptin (see Glaum et al., Mol. Pharmacol., 50:230-5, (1996); Spanswick et al., Nature, 390:521-5, (1997)) and demonstrated colocalization GABA and NPY (see Horvath et al., Brain Res., 756:283-6, (1997)) in subpopulations of neurons in the ARC led to the assumption that leptin causes hyperpolarization of the cell NPY/GABA, which directly innerviews neurons O.G. ROMs and, thus, reduces GABAergic effects on cells O.G. ROMs. Both leptin and Y2 receptors are expressed NPY neurons containing NPY in the ARC (see Hakansson et al., J. Neurosci. 18:559-72, (1998); Broberger et al., Neuroendocrinology, 66:393-408, (1997)). Moreover, activation of Y2 receptors inhibits the release of NPY neurons containing NPY (see King et al., J. Neurochem., 73:641-6, (1999)) and probably also minimizes the release of GABA from the end of the NPY/GABA. This gives an alternative pharmacological approach, independent of leptin to test hypothetical innervation of neurons O.G. ROMs GABAergic neurons containing NPY. Indeed, NPY (at a concentration of 100 nm; Bachem) reduces the frequency of GABAergic IPSCs by 55% within 3 minutes in all 12 investigated cells O.G. ROMs (see Figure 4A). Both NPY and leptin, in addition, inhibit IPSCs in the presence of tetrodotoxin (TTX) (6 of 6 and 3 of the 5 cells, respectively), showing that some inhibition of IPSCs due directly the governmental effects on presynaptic nerve endings. Neurons O.G. ROMs Express the receptor for NPY Y1 (see Broberger et al., Neuroendocrinology, 66:393-408, (1997)) and NPY also causes hyperpolarization of all tested neurons O.G. ROMs on average 9±6 mV (n=3).

Other pharmacological test to confirm the nature of GABAergic innervation in the neurons O.G. ROMs with endings NPY/GABA is a testing effect recently characterized and highly selective agonist MC3-R D-Trp⁸-γMSH (see Grieco et al., J. Med. Chem. 43:4998-5002, (2000)) local output GABA. D-Trp⁸-γMSH (at a concentration of 7 nm) increases the frequency of GABAergic IPSCs (280±90%)registered for 3 of the 4 neurons O.G. ROMs (see Figure 4b). It doesn't work on one cell. The positive effect of the activation of the MC3-R together with the negative effects of NPY and leptin demonstrates the dynamic range of a synapse NPY/GABA on neurons O.G. ROMs and indicates an important role of this synapse in the modulation of the conduction signal in the ARC. D-Trp⁸-γMSH (at a concentration of 7 nm) also causes hyperpolarization (-5,5±2.4 mV) 9 out of 15 investigated neurons O.G. ROMs and reduces the frequency of action potentials (see Figure 4C). In other cells, no significant response to D-Trp⁸-γMSH. These effects may not be entirely due to the increased output Gamka cells O.G. ROMs and could be associated with additional postsynaptic action of D-Trp⁸-γMSH on neurons in the MHI, among them, about half also expresses MC3-R (see Bagnol et al., J. Neurosci. (in press), 19:RC26, (1999)). So, MC3-R a similar MOP-R autoreceptors on neurons O.G. ROMs, reducing to a minimum the activity of neurons O.G. ROMs in response to elevated levels of peptides O.G. ROMs.

To further define what IPSCs in neurons O.G. ROMs determined by the local innervation cells NPY/GABA, carried out the immunohistochemical studies with multiple labels using light and electron microscopy. Although described independent NPY innervation (see Csiffary et al., Brain Res., 506:215-22, (1990)) and GABA (see Horvath et al., Neuroscience, 51:391-9, (1992)) on the cell O.G. ROMs, colocalization NPY and GABA in the synapses, forming the nerve endings, not shown. Similarly to rats (see Csiffary et al., Brain Res., 506:215-22, (1990)), the dense innervation of cells O.G. ROMs endings of axons NPY was detected in mice (see Figure 4d). The electron microscopy data confirmed coexpressing NPY and GABA in the endings of axons and show that these synapses, forming a "buds" (complexes), on the periphery of the 15 analyzed neurons O.G. ROMs ARC (a representative example, see Figure 4E).

On a detailed model of the regulation of this cycle shows the pair of mechanisms of action of leptin in the ARC, interactions between NPY/GABA and neurons O.G. ROMs and autoregulatory back the Oh connection with opioid and melanocortin peptides, and NPY (see Figure 4f). In this model, leptin directly induces depolarization of neurons O.G. ROMs and simultaneously hyperpolarization of the soma of neurons and reduces the release of their endings NPY/GABA. This reduced the release of GABA relieves inhibition of neurons O.G. ROMs and results in activation of neurons O.G. ROMs and increased the frequency of action potentials.

Example 3

Introduction PYY inhibits the absorption of food

System orexigenic NPY and anorectics α-melanocortin-stimulating hormone (α-MSH) in the arcuate nucleus of the hypothalamus are involved in the Central regulation of appetite (see Schwartz et al., Nature, 404:661-671, (2000)). However, potential mechanisms of signal transmission, absorption of food directly in the data hypothalamic closed the food chain remain unclear. PYY_3-36represents isolated from the gut hormone that is released after a meal in proportion to the number of consumed calories (see Pedersen-Bjergaard et al., Scand. J. C1in. Lab. Invest., 56:497-503, (1996)). Examine the effects of peripheral injection of PYY3-36 on food.

Intraperitoneal injection (IP) PYY_3-36rats with a regime of free food before the onset of the dark phase significantly reduces the subsequent absorption of food (see Figure 5A). A similar suppression of power observed after IP injection in rats subjected to fasting for 24 hours (the m Figure 5b). In terms of time levels of PYY_3-36in plasma is reached after IP injection of PYY_3-36demonstrate peak level 15 minutes after injection, which lies in the range of normal levels after a meal (peak levels of PYY_3-3615 minutes after IP injection of 0.3 ág/100 g=99,3±10.4 pmol/l compared to the peak level after a meal=112,1±7.8 pmol/l n=8-10/group). This suggests that physiological concentrations of PYY_3-36suppress food. PYY_3-36no effect on gastric emptying (the percentage of the absorbed food remaining in the stomach after 3 hours is for PYY_3-36=36±1,9%saline solution=37,4±1,0% (n=12) (see Barrachina et al., Am. J. Physiol., 272:R1007-11, (1997)). PYY_3-36intraperitoneal injection twice a day for 7 days reduces the cumulative absorption of food (7-day cumulative absorption of food is for PYY3-36=187,6±2.7 g relative to the data for saline=206,8±2,3, n=8/group, P<0,0001) and reduces the weight of the body (see Figure 5d) (PYY_3-36=48,2±1.3 g relative to saline=58,7±1,9, n=8/group, P<0,002).

Example 4

Introduction PYY acts on the expression of c-fos

To study whether this suppression of food intake hypothalamic path, exploring the expression of c-fos in the arcuate nucleus, an important centre of power control (smstate Schwartz et al., Nature, 404:661-671, (2000); Cowley et al., Nature, 411:480-484, (2001)) after a single intraperitoneal injection of PYY3-36. In the lateral arc of rats noted a twofold increase in the number of cells positive for c-fos (PYY3-36=168±2, saline=82,7±5, n=3, P<0,0001). Similarly, in transgenic mice Pomc-EGFP (see Cowley et al., Nature, 411:480-484, (2001)) intraperitoneal injection of PYY_3-36inthe result leads to an increase of 1.8 times the number of cells arc, positive for c-fos (see Figure 6b) compared with the control animals, which are injected with saline (see Figure 6A) (PYY_3-36=250±40, saline=137±15, n=5, P<0,05). IP introduction PYY_3-36increases 2.6 times the ratio of neurons O.G. ROMs, which Express c-fos (PYY_3-36=20,4±2.9 per cent, saline=8±1,%, n=5, P<0,006) (see Figures 6C and d).

These observations suggest that PYY_3-36may act through the arcuate nucleus. Consequently, study PYY_3-36and its effects on the way NPY and O.G. ROMs in the hypothalamus. Due to the delayed suppression of food and the effects of weight gain after peripheral injection of PYY_3-36hypothalamic messenger RNA (mRNA) as Pomc and NPY was measured using assays RNase protection. A significant reduction in NPY mRNA in response to PYY_3-36see 6 hours after IP injection compared to animals, coloringpages saline (saline=17,3±2,0, PYY3-36=8,8±1,0, relative units of optical density, P<0,02). Note the slight increase in mRNA levels O.G. ROMs.

Example 5

Receptors Y2

PYY_3-36shows 70% identity of amino acid sequence with NPY and operates through the NPY receptors (see Soderberg et al., J. Neurochem., 75:908-18, (2000)). Y2R presumably an inhibitory presynaptic receptor and is expressed at high levels in neurons containing NPY, in the arcuate nucleus (see Broberger et al., Neuroendocrinology, 66:393-408, (1997)), although not expressed on neighboring neurons O.G. ROMs. PYY_3-36is a high-affinity agonist of the receptor Y2 (Grandt et al., Regul. Pept, 51:151-159, (1994)). Assume that the peripheral PYY_3-36inhibits the absorption of food through Y2R in the arcuate nucleus, an area known as directly accessible to the action of hormones circulating in the blood (see Kaira et al., Endocr. Rev., 20:68-100, (1999)).

To study this hypothesis PYY_3-36injected directly into whooopeee kernel (see Kim et al., Diabetes, 49:177-82, (2000)). Rats subjected to starvation for 24 h, the absorption of food is greatly reduced at such low doses as 100 fmol (see Figure 7a), which in result leads to the suppression, similar to the observed after IP injection. In order to determine whether mediated by these effects through Y2R, use the Ute selective Y2R agonist (see articles Potter et al., Eur. J. Pharmacol., 267:253-262, (1994)), N-acetyl (Leu 28, Leu 31) NPY24-36) [Y2A]. His affinity is confirmed in studies of the binding of the receptor (see Small et al., Proc. Natl. Acad. Sci. U.S.A., 94:11686-91, (1997)cell lines expressing the NPY receptors Y1, Y2 and Y5 Y2 has the IC₅₀=1,3+0,2 nm, IC₅₀Y1>5000 nm, IC₅₀Y5>5000 nm). Introduction Y2A in whooopeee the nucleus of rats previously subjected to starvation for 24 hours in a dose-dependent manner (100 fmol - 1 nmol) inhibits the absorption of food (intake 2 hours after injection is 0.1 nmol Y2A=6,2±0,5 g to physiological saline=8,2±0.6 g, n=8/group, P<0,05).

To confirm the anatomical specificity of this effect Y2A (100 fmol - 1 nmol) injection is injected with paraventrikulyarnoe core (VAT) (see Kim et al., J. C1in. Invest., 105:1005-11, (2000)) rats subjected to starvation for 24 hours, and do not detect changes in the absorption of food (2 hours after injection: saline=8,3±0.4 g, 0.1 nmol Y2A=8,0±0.6 g, n=8/group). To further define the role of Y2R in the suppression of power caused by peripheral introduction PYY_3-36examine the effect of PYY_3-36in mice with absence of Y2r and control offspring. PYY_3-36suppresses feeding in the daytime dose-dependent manner have been fasting male wild-type mice, but does not inhibit the absorption of pixiu subjected to fasting mice with absence of Y2R (see Figures 7b and 7C). The absorption of food, measured as a response to starvation, demonstrates that male mice with absence of Y2r eat much more after 2, 4 and 24 hours compared with control offspring (24-hour cumulative absorption of food; mouse with no Y2R=7,1±0,48 g relative to wild-type=5,3±0.7 g, n=8/group, P<0,05).

Explore the electrophysiological response of hypothalamic neurons O.G. ROMs on introduction as PYY_3-36and Y2A. These neurons identified using mice with targeted expression of the protein of green fluorescence in neurons O.G. ROMs (see Cowley et al., Nature, 411:480-484, (2001)). PYY_3-36relieves inhibition of neurons O.G. ROMs that results in a significant depolarization of 19 of the 22 investigated neurons O.G. ROMs (see Figure 8A, inset), (depolarization 10,3+to 2.1 mV, n=22, P < 0,0003). Such depolarization observed when using Y2A (depolarization of 8.7±1.8 mV, n=9, P<0,002). The depolarization caused by PYY_3-36stimulates a significant increase in the frequency of action potentials in neurons O.G. ROMs (see Figure 8A) (93% increase relative to control, P<0,05, n=22). In the format intact cells the effect of PYY_3-36sometimes withdraw money, but only after a long delay (30 minutes). These neurons are seeing similar effects similar laundering leptin.

To exclude effects of depletion cleto who or damage the integrity investigate the effect of PYY _3-36configuration by attaching free cells (or extracellularly configuration). PYY_3-36causes reversible 5-fold increase in the frequency of action potentials in the registration records of neurons O.G. ROMs when using attaching free cells (see Figure 8b). This increase in the number of excitation pulses occurs with the same delay with which PYY_3-36reduces the frequency of brake postsynaptic currents (IPSCs) in all 13 of the investigated neurons O.G. ROMs (see Figure 8C) (decrease 51,9±9,2%, n=13; P<0,0001), indicating a lower output frequency of GABA neurons O.G. ROMs. Interestingly, the number of pulses of neurons O.G. ROMs returns to the base level, despite the continuous inhibition of IPSCs. A similar effect in relation to the frequency of IPSC see when using Y2A (decrease 44,4+9,3%, n=8, P<0.004 percent), suggesting a mediating this effect through Y2R. PYY3-36 (at a concentration of 25 nm) causes a hyperpolarization (5,2±1,16 mV, P<0.004 percent, n=5) unidentified, but presumably containing NPY neurons in the not-O.G. ROMs in the arcuate nucleus. Mark tonic GABAergic inhibition of neurons O.G. ROMs neurons containing NPY (see Cowley et al., Nature, 411:480-484, (2001)), and these results suggest that the effect of PYY_3-36is the inhibition of neurons containing NPY neurons, and the reduction of such clicks the zoom GABAergic signal, and therefore, removing the inhibition of neurons O.G. ROMs. Examine also the effect of Y2A on the secretion of the peptide using hypothalamic explants (see Kim et al., J. Ctin. Invest., 105:1005-11, (2000)). Y2A significantly reduces the release of NPY while at the same time increase the yield of a-MSH from hypothalamic explants (see Figures 8d and 4E). Taken together, these observations suggest that PYY_3-36modulating system as NPY and melanocortin in the arcuate nucleus.

Example 6

Human studies

Due to the importance melanocortin system for humans (see Barsh et al., Nature, 404:644-651, (2000)), and the profound effects of PYY_3-36as to food, and the change in body mass observed in rodents, examined the effects of PYY_3-36on appetite and absorption of food in humans. Twelve subjected to starvation without obesity voluntary participants (six men and six women, mean age 26,7±0,7 years, BMI = 24,6±0,94 KGM^-2make an infusion of PYY_3-36(0.8 Polk^-1Min^-1) or saline for 90 minutes in the double-blind study a mixed method with the control in the form of a placebo.

Concentrations of PYY_3-36in plasma increased from an average baseline concentration of 8.3±1,0 PM to 43.5±3 PM during infusion of PYY_3-36and imitate levels after a meal (see article PedersenBjergaard et al., Scand. J C1in. Lab. Invest., 56:497-503, (1996), Adrian et al., Gastroenterology, 89:1070-1077, (1985)). Concentrations of PYY_3-36achieved after infusion return to baseline within 30 minutes. Infusion of PYY_3-36it results in a significant reduction evaluation hunger (see Raben et al., Br.J. Nutr., 73:517-30, (1995)) (see Figure 9c)none cause drowsiness or weakness. The consumption of calories with a free choice of snacks (see Tarling et al., Intensive Care Med., 23:256-260, (1997)) in two hours after the infusion is reduced by more than one-third relative to saline (36±7,4%, p<0,0001) (see Figure 9a). There is no effect on the absorption of fluid and differences in the feeling of satiety and nausea, described the voluntary participants in the experiment. Introduction PYY_3-36no effect on gastric emptying, as determined by the method based on the absorption of paracetamol (see Edwards et al., Am. J. Physiol. Endocrinol. Metab., 281:E155-E166, (2001); Tarling et al., Intensive Care Med., 23:256-260, (1997)) or the level of glucose in plasma leptin levels of GLP-1 or insulin in plasma. The analysis of diaries power shows significant suppression of food intake during the 12-hour period after infusion of PYY3-36 (saline=2205±243 kcal, PYY3=1474±207 kcal). However, the absorption of food in the period between 12 and 24 hours is virtually identical in the two groups. In General, see 33% reduction in the cumulative total the consumption of calories per 24-hour period after infusion of PYY _3-36(see Figure. 9b). These facts demonstrate that the infusion of PYY_3-36at concentrations corresponding to levels after eating causes significant suppression of appetite and food intake in humans.

Additional study involved two groups of healthy subjects (n=12/group, 6 men and 6 women), one of the subjects with a high body mass index (BMI) (mean index = 32,73±0.93 kg/m²and another group of subjects with low BMI (mean index = 20,49±2,05 kg/m²). Group study twice with an interval of at least 1 week between each of the studies. All subjects fast and drink only water from 20:00 h in the evening prior to each study. Subjects arrived at 08:30 each day of research, they introduce the cannula and allow to rest for 30 minutes before the start of the study Protocol. Subjects injected with either saline or 0,8 Polk^-1Min^-1PYY_3-36within 90 minutes in a double-blind randomized mixed format. Two hours after the end of infusion to subjects offer a free choice of snacks in abundance, so that you can satisfy all appetites. Food and water are weighed before and after food intake and calculate the caloric intake. The number of calories consumed after the introduction of saline solution and PYY_3-36CPA is Nivat using paired student test (p< 0,001). The number of calories consumed after administration of PYY_3-36significantly different from the number of calories consumed after injection of saline into two groups - group with overweight and a group of lean subjects (subjects without overweight). For a group with overweight shown a reduction of 28.8±4.3% and for the group without the excess weight reduction by 31.1±4.4 per cent. However, the reduction in the group with excessive body weight has no significant difference with the reduction in the group without overweight. These facts demonstrate that the infusion of PYY_3-36at concentrations corresponding to the levels after eating causes significant suppression of appetite and food intake in both subjects with overweight and having excess body weight.

Regardless of theory, the cells in the arcuate nucleus could determine peripheral signals of saturation and to transmit data signals to other brain areas (see Butler et al., Nature Neuroscience, 4:605-611, (2001)). This assumption is supported by the observation that leptin modifies the activity of neurons in the arcuate nucleus O.G. ROMs containing NPY (see Cowley et al., Nature, 411:480-484, (2001)). The results presented in this context, demonstrate on the basis of complex electrophysiological studies and the waves of hypothalamic explants, that the intestinal hormone PYY_3-36can directly affect hypothalamic cycles that results in the coordinate changes in action O.G. ROMs and NPY. The presented results show that neurons containing NPY in ARC not protected by the blood-brain barrier and, therefore, accessible to the impact of molecules circulating in the circulatory system. Moreover, PYY_3-36entered directly in this area of the brain, reduces the absorption of food.

The results presented in this context, demonstrate that the levels of PYY_3-36after eating inhibit the absorption of food from more than one species of mammals (for example, in rodents and humans) for a period of up to 12 hours, thereby illustrating their role in the regulation of food intake. This role can be defined as the long-acting effect, such as continuing for several hours (for example, at least two, three, four, eight or twelve hours, or from about two to about fifteen hours). These compounds differ from the previously described isolated from the guts of signals "short-term" saturation, such as cholecystokinin (see Schwartz et al., Nature, 404:661-671, (2000); Moran, Nutrition, 16:858-865, (2000), the effects are relatively short-lived (for example,from about 1 to 4 hours).

The inability of PYY_3-36to suppress the absorption of food in mice Y2R-null proves that PYY_3-36reduces the absorption of food through Y2R-dependent mechanism. The results presented in this context, we assume the existence of a new enteric-hypothalamic pathway in the regulation of food, including the effect of PYY_3-36on the level after eating Y2R in the arcuate nucleus. Thus, PYY and its analogues, such as PYY_3-36are therapeutic agents for the treatment of obesity.

There is no doubt that the exact details of the described methods and compositions can be changed or modified within the entity described invention. Claimed all of these modifications and variants, which are included in the scope and essence of the following claims.

1. Modification of eating behavior, characterized in that the conduct of the peripheral introduction to the subject of PYY in amounts effective to achieve the physiological levels of PYY_3-36in blood, plasma or serum, determined after a meal, or have peripheral introduction to the subject of PYY agonist in an amount effective to simulate physiological levels of PYY_3-36in blood, plasma or serum, determined after a meal with a modification of eating behavior, by reducing calorie consumption PI and or loss of appetite or increase energy consumption at the subject.

2. The method according to claim 1, characterized in that the subject is overweight.

3. The method according to claim 1, wherein the subject suffers from obesity.

4. The method according to claim 1, wherein the subject suffers from diabetes.

5. The method according to claim 1, characterized in that the peripheral introduction PYY or PYY agonist include oral, subcutaneous, intravenous, intramuscular, intranasal, dermal, intracisternally, endovaginal, intraperitoneal, local, cressilia, buccal, rectal or sublingual introduction or introduction via pulmonary inhalation.

6. The method according to claim 5, characterized in that the dose of PYY or the agonist is from about 45 to about 135 pmol/kg body weight of the subject.

7. The method according to claim 6, characterized in that the dose of PYY or the agonist is approximately 72 pmol/kg body weight of the subject.

8. The method according to claim 1, wherein the PYY or agonist is administered at least 30 minutes before eating.

9. The method according to claim 1, characterized in that the peripheral introduction PYY or agonist perform many times, and each dose is administered in an amount of from about 0.5 to about 135 pmol/kg body weight of the subject at least approximately 30 minutes before a meal.

10. The method according to claim 1, wherein the subject is also administered a therapeutically effective number is the number of additional agent, suppressing appetite, which is a amfepramone (diethylpropion), phentermine, mazindol, phenylpropanolamine, fenfluramine, dexfenfluramin or fluoxetine.

11. The method according to claim 1, wherein the PYY or agonist is administered to a subject in amounts effective to reduce the consumption of calories for at least 2 hours.

12. The method according to claim 11, wherein the PYY or agonist is administered to a subject in amounts effective to reduce the consumption of calories for about 2 to 24 hours.

13. The method according to claim 1, wherein the subject is human.

14. The method according to claim 1, wherein the PYY agonist contains a molecule that specifically binds with a Y2 receptor.

15. The method according to 14, wherein the PYY agonist increases the expression of c-fos in the part of the arcuate nucleus in contact with the PYY agonist.

16. The method according to claim 1, wherein the PYY agonist specifically binds to a neuron, containing neuropeptide Y, and inhibits the activity of neurons that contain neuropeptide Y.

17. The method according to item 16, wherein the PYY agonist reduces the pulse frequency of the action potential of a neuron, containing the neuropeptide Y.

18. The method according to item 16, characterized in that the neurons containing neuropeptide Y, synaptic associated with proopiomelanocortin neuron, is that the binding of agonist PYY c neuron, containing neuropeptide Y, leads to increased activity proopiomelanocortin neuron.

19. The method according to p, wherein the PYY agonist, binding to neurons containing neuropeptide Y reduces the pulse frequency of the action potential of a neuron, containing neuropeptide Y, thus reducing the activity of neurons that contain neuropeptide Y, leads to increased generation of action potential proopiomelanocortin neuron.

20. The method according to claim 1, characterized in that reach of loss of appetite in the subject.

21. The method according to claim 20, characterized in that reach of the reduction in food intake by the subject.

22. The method according to item 21, wherein achieve reduction of calorie intake by the subject.

23. The method according to claim 1, characterized in that the reach of prevention or reduction of the set of body weight of the subject.

24. The method according to claim 1, characterized in that reach induce or sustain loss of body weight of the subject.

25. The method according to claim 1, wherein the PYY or agonist is administered in an amount of from about 0.5 to about 135 pmol/kg body weight of the subject.

26. The method according to claim 1, characterized in that reach of inducing or enhancing satiety and feeling of satiety in the subject.

27. The method according to claim 1, characterized in that reach suppress hunger and sensations of hunger in the subject.

2. The method according to claim 1, characterized in that the peripheral introduction to the subject of the PYY or agonist perform repeatedly or in separate doses.

29. The method according to claim 1, characterized in that the peripheral introduction to the subject of the PYY or agonist perform peripheral injection pulse dose.

30. The method according to claim 1, characterized in that the peripheral introduction PYY or the agonist is carried out in a manner that provides slow, prolonged or controlled release of drugs, or by means of a pump or implantable device for injecting drugs.

31. The method according to claim 1, characterized in that the conduct of the peripheral introduction PYY or agonist at a dose of from about 5 to about 50 nmol.

32. The method according to claim 1, characterized in that the dose of PYY or the agonist is from about 2 to about 20 nmol.

33. The method according to p, characterized in that the dose of PYY or the agonist is approximately 10 nmol.

34. The method according to claim 1, wherein the subject is administered a therapeutically effective amount of an additional agent that suppresses the appetite.

35. The method according to claim 1, wherein the subject is further added at least one agent that reduces the level of glucose in the blood plasma, agents that modify the content of lipids in the plasma to the JVI, or agents that reduce food intake.

36. The method according to claim 1, wherein the subject has reached maintain the desired body weight or maintain a desirable body mass index.

37. The method according to claim 1, wherein the subject suffers from a disorder or at risk in respect of breach, a risk factor is obesity or overweight.

38. The method according to claim 1, wherein the subject suffers the violation caused, complicated or aggravated due to relatively high nutrient availability.

39. The method according to claim 1, wherein the subject suffering from a disorder caused, complicated or aggravated due to relatively high nutrient availability, enter the PYY agonist.

40. The method according to claim 1, characterized in that the physiological levels of PYY_3-36in the blood, serum or plasma after a meal ranges from 40 to 60 PM.

41. The method according to p, characterized in that the physiological levels of PYY_3-36in the blood, serum or plasma after a meal ranges from 40 to 50 PM.

42. The method according to claim 1, wherein the PYY is a PYY_3-36.

43. The method according to § 42, wherein the PYY_3-36enter in the amount of from about 0.5 to about 135 pmol/kg body weight of the subject.

44. The method according to § 42, characterized in that Thu is PYY _3-36enter in the amount of from about 45 to about 135 pmol/kg body weight of the subject.

45. The method according to § 42, wherein the PYY_3-36enter in the amount of approximately 72 pmol/kg body weight of the subject.

46. The method according to § 42, wherein the PYY_3-36enter a number from about 1 to about 100 nmol.

47. The method according to claim 1, wherein the subject is administered PYY.

48. The method according to claim 1, wherein the subject is administered PYY agonist.

49. The use of PYY or the agonist as a means for modification of eating behavior with the goal of reducing weight in a subject by decreasing calorie intake, food intake, or appetite or increase energy consumption at the subject.

50. The use of PYY or the agonist as an active ingredient in the manufacture of a medicinal product for modification of eating behavior with the goal of reducing weight in a subject by decreasing calorie intake, food intake, or appetite or increase energy consumption at the subject.