The agent with antidepressant and neuroprotective activity


(57) Abstract:

The invention relates to medicine, namely to pharmacology. The proposed means of N-acetyl-DL-aspartic acid, which has antidepressant and neuroprotective activity, which can be used as a medicine in the treatment of mental illness. table 4.

The invention relates to the chemistry of amino acids and their derivatives, namely N-acetyl-DL-aspartic acid formula

HOOC-CHOH which the disodium salt has antidepressant and neuroprotective activity.

Known antidepressant and neuroprotective drugs used currently for the treatment of mental illness, have a number of significant drawbacks.

For example, drug hydrochloride formula

is one of the most effective antidepressants that also provides additional psychoactive effect. However, imipramine cause numerous side effects: headaches, dizziness, ataxia, cardiac arrhythmias, skin allergic reactions, constipation, etc. [Mashkovsky M. D. Pharmacology of antidepressants. M. Medicine, 1983, S. 174; Mashkovsky M. D. Medicines, T. 1, M Medicine, 1986, S. 94]

Known nootropic agent piracetam [Mashkovsky M. D. Medicines. So 1. M. Medicine, 1986, S. 117] formula

is not sufficiently effective for the correction memory in persons of old age, suffering from degenerative and sclerotic lesions of the brain [Heise, G. A. Trends Pharmacol. Sciene, 1987, v. 8, R. 65-68] This is reflected in the experimental studies, which show that piracetam does not eliminate memory impairment model scopolamine amnesia corresponding to memory impairment in persons in old age [Petkov V. Vuglenova Y. Acta physiol. pharmacol. Bulg. 1985, v. 11. p 37; Tobe A. Yamaguchi T. Nagai R. Egava M. Jap. J. Pharmacol, 1985, v. 39, R. 153-161]

Aspartic acid and some of its derivatives exhibit high biological activity.

-Alkalemia esters of aspartic acid and its 2-alkyl derivatives of General formula

HOOC-CH2-)-COO-R2where R1, R2H, alkyl

used as antihypertensive drugs [U.S. Pat. USA N 4065572 (1977), CL 424/273 R]

A dipeptide of aspartic acid, e.g/112.5 R (1982)] or other lower alkalemia ester-L-aspartyl-L-phenylalanine [U.S. Pat. USA N 4332718, CL 260/112.5 R (1982)] are used as sweeteners.

The diamide N-acylaminoacyl, including aspartic acid of General formula

(CH3)2N--(CH2offered as an oral anti-ulcer drug [jap. application N 57-134452, class C 07 C 103/84, A 61 K 31/165 (1983)]

N-phosphonacetyl-L-aspartic acid formula

HOOC-CH disodium or TETRANITRATE salts inhibit the biosynthesis of pyrimidine nucleotides and shows antitumor activity [U.S. Pat. USA N 4267126, CL 260/942 (1981); the Application of Germany N 2752287, class C 07 C 101/22 (1979)]

N-Acetylaspartate acid is a product of the metabolism of nerve tissue and is found in large quantities in the brain [Trackenmiller M. E. J. Neurochem. 1985m c. 45, p. 1658-1662] However, the functional role of N-acetylcarnosine acid metabolism in brain tissue remains unclear. It has been suggested that N-acetylcarnosine acid involved in the biosynthesis of acetylcholine and myelin in neurons, promotes the release of excitatory amino acids-mediators. The content of N-acetylcarnosine acid in the brain changes in traumatic brain injury and other pathological effects [Crafts M. W. Exchange wiseana glutamatergic synapses. L. Science, 1987, S. 50] Information about pharmacological effects, in particular, on the study of the antidepressant and neuroprotective activity of N-acetylcarnosine acids are missing.

As the base object for the antidepressant activity of selected drug imipramine widely used in the depressed state of various etiologies, for example, endogenous depression, involutional menopause depression, depression with personality disorder, neurosis, as well as with alcoholic depression. A significant drawback of imipramine are numerous side effects: headaches, dizziness, ataxia, arrhythmia, skin allergic reactions, constipation, retention of urine, sweating, accommodation disorder, insomnia, etc. [Mashkovsky M. D. Medicines. So 1, M Medicine, 1986, S. 94]

As the base object for nootropic activity of selected drug is piracetam used for memory impairment, cerebral blood flow insufficiency, chronic alcoholism, head injuries, and so on [Mashkovsky M. D. Medicines. So 1. M: Medicine, 1986, S. 117] the Disadvantage of piracetam is its low efficiency in the correction memory in individuals old the completion of the present invention is to develop a new low-toxic psychotropic drug with the antidepressant and neuroprotective activity.

The essence of the invention lies in the use of N-acetyl-DL-aspartic acid disodium salt as a psychotropic agent with antidepressant and neuroprotective activity.

Synthesis of N-acetyl-DL-aspartic acid is performed by the acetylation of DL-aspartic acid with acetic anhydride in the environment of glacial acetic acid at 80-100aboutC.

P R I m e R 1. N-Acetyl-DL-aspartic acid. 20,0 g (0,150 mol) of DL-aspartic acid and 17.5 ml (0,185 mole) of acetic anhydride and 150 ml of glacial acetic acid is stirred at a temperature of 80-90aboutC for 4 h, cooled, filtered off the insoluble impurities, acetic acid and excess acetic anhydride is distilled off in a boiling water bath in a vacuum, getting to 24.6 g of vitreous light-yellow substance, the yield of 93.5%

PMR-spectrum , M. D. 1,90 (3H), 2,89 d (7 Hz, 2H); 4,89 kV (7 Hz, 1H); (Tesla BS-A, 100 MHz, 20% solution in dimethylformamide D7).

P R I m m e R 2. N-Acetyl-DL-aspartic acid, 25,0 g (0.147 mol) of the hydrochloride DL-aspartic acid, 12.5 g (0,152 mol) of sodium acetate, 17.5 g (0.185 mol) of acetic anhydride and 150 ml of glacial acetic acid is strong acid and excess acetic anhydride is distilled off in vacuum on a boiling water bath, the release of N-acetyl-DL-aspartic acid 23.7 g (92.1 per cent).

P R I m e R 3. The disodium salt of N-acetyl-DL-aspartic acid (ACAC). 10.0 g (0,057 mol) of N-acetyl-DL-aspartic acid and 4.5 g (0,113 mol) of sodium hydroxide dissolved under cooling in 50 ml of water and adjusted pH to 11-12 by adding 20% sodium hydroxide solution. Add 2 g of activated carbon, stirred for 10 min at room temperature, filtered, the filtrate was poured with stirring into 250 ml of acetone emitted yellow oil three times triturated with 50 ml of anhydrous acetone and dried in vacuum at a residual pressure of 1-2 mm RT.article and a temperature of 100-120aboutWith getting 12.2 g of light yellow crystalline hygroscopic product, deliquescent in the air.

We investigated the antidepressant and neuroprotective activity of disodium salt of N-acetyl-DL-aspartic acid (ACAC). The study of psychotropic activity of ACAC were carried out on outbred rats-males weighing 150-200 g and mice-males 18-20 g, were obtained from the nursery of AMS USSR "White moss".

The influence of Azak on spontaneous locomotor activity and orienting-exploratory behavior of animals studied in the open-field test. Installing the open field was krupppresta conducted under illumination platform 60 Lux and recorded the following indicators of animal behavior: the number of crossed squares (locomotor activity), the number of stevani on his hind legs and zaglyadyvanie in holes (approximately research activity) and the number of defecations (emotionality). After 1 h after intraperitoneal administration of Azak at doses of 10 and 50 mg/kg had no effect on the behavior of rats in the open-field test, and in a dose of 100 mg/kg increased orienting-exploratory activity (number of stevani on his hind legs) and emotional level (the number of defecations) animals (table.1).

For the study of the antidepressant activity of ACAC used method [Porsolt R. D. Bertin A. Yalfre M. Arch. Int. Pharmacodyn. Ther. 1977, v. 229, p. 327-333] modification [Schmidt J. Biomed. Biochim. Acta. 1985, v. 44, p. 755=761] according to which the main indicator of "behavioral despair" of mice is the time of immobilization (negative finding a way out of the vessel filled with water). The reduction in the duration of immobilization was regarded as a manifestation of the antidepressant activity of the substance. The results of the study of the antidepressant activity of ACAC test "behavioral despair in mice are presented in table.2. ACAC at doses of 1, 50 and 100 mg/kg significantly reduced the duration of immobilization of animals that can be considered by increasing the activity of mice in search of an exit from aversive situations is nteu activity ACAC as the comparison drug was selected antidepressant imipramine, widely used currently in clinical practice. Test "behavioral despair", which is most often used to evaluate the antidepressant activity, imipramine has a strong antidepressant effect in the dose of 10 mg/kg, which is about 1/7 of the LD50. ACAC shows antidepressant activity, 3-4 times larger than the activity of imipramine, in doses of 1, 50 and 100 mg/kg, which is only 1/2660-1/26 from LD50, i.e., in doses of 3.7 380 times less toxic than the reference drug.

The study of the neuroprotective activity of ACAC conducted on the model of the violation of the conditional reaction passive avoidance (passive avoidance reaction). As amnestic effects used the introduction of M-cholinolytic of scopolamine dose of 1.5 mg/kg over 30 min to play passive avoidance reaction [Tobe A. Yamaguchi T. Nagai R. Egawa M. Jap. J. Pharmacol, 1985, v. 39, p. 153-161] Evaluation antiamnesic effect of tested compounds was carried out according to two indicators of passive avoidance reaction latency period of time in the dark compartment and the time spent in the dark compartment. The comparison of the neuroprotective properties of ACAC conducted with the reference drug piracetam, widely used in the clinic as a neuroprotective agent. Data about the antiamnesic effect of piracetam taken from the property.

The introduction of scopolamine dose of 1.5 mg/kg over 30 min to play passive avoidance reaction caused memory impairment in animals, which was reflected in the reduction of latency period of time in the dark compartment and increase the time spent in the dark compartment. ACAC at a dose of 10 mg/kg had no effect, and at a dose of 50 mg/kN increased the latent period of time in the dark compartment and reduced the time spent on it compared to a group of animals, which were introduced only scopolamine (PL.3). This suggests that Azak has antiamnesic effect on the model scopolamine amnesia. This model is often used to study the neuroprotective activity of the compounds [Methodical recommendations for a pilot study of drugs with neuroprotective action type. M. Medicine, 1986, S. 11] and adequate memory impairment in humans during aging [Bartus R. T. Dean, R. L., Beer, B. A. S. Lippa Science, 1982, v. 217, p. 408-414] the Reference drug piracetam dose of 100 mg/kg, which is 2-5 times higher than therapeutic doses, does not resolve the amnesia passive avoidance reaction caused by scopolamine (PL.3).

The results of determination of the acute daily toxicity (LD50) studied substances on white outbred mice with intraperitoneal injection method Prozorovsky Century B. [Prozorovsky Century B. Prozorovskaya M. P. FA is it toxic, than imipramine, surpasses it in 3-4 times the antidepressant activity at doses of 1-100 mg/kg, and at a dose of 50 mg/kg exceeds piracetam for nootropic activity model violations passive avoidance reaction, with the introduction of scopolamine. The combination of expressed antidepressant and neuroprotective properties of N-acetyl-DL-aspartic acid makes it possible to consider this compound is promising for the treatment of a wide range of mental illnesses.

The use of N-acetyl-DL-aspartic acid as an agent with antidepressant and neuroprotective activity.


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