Peptide having neurotropic activity

FIELD: chemistry.

SUBSTANCE: present invention relates to bioorganic chemistry and medicine and can be used to prepare medicinal agents with neurotropic activity. The technical result is achieved due to creation of a peptide with neurotropic activity and having general formula: Ac-X-Met-Pro-Arg-Gly-NH2, where X-Met - L-Met or DL-Met.

EFFECT: obtaining a novel compound - analogues of the C-terminal end of vasopressin which are capable of selectively bonding with different subtypes of vasopressin receptors and, as a result, have different types of neurotropic activity, have low toxicity and are suitable for simple intranasal administration.

5 ex

 

The invention relates to the field of Bioorganic chemistry and medicine and can be used to create drugs with neurotropic activity.

It is known that neurohypophyseal hormone vasopressin has behavioral activity, as a stimulator of memory and learning [1, 2]. However, it has a wide spectrum of biological activity and in medicine is used primarily as a hormonal agent that regulates blood pressure, diuresis.

Known testisterone peptides that are fragments of the C-terminal sequence of vasopressin stimulating learning laboratory animals at doses 100-1000 times higher doses of vasopressin in similar tests, but deprived of its hormonal effects [3, 4].

Known peptides are C-terminal fragments of vasopressin containing cysteine, more synthetically available [5, 6]. The most active stimulant memory and learning from them is tetrapeptide Cys-Pro-Arg-Gly-NH2effective dose which is comparable with the doses of vasopressin.

Along with natural peptides sequences obtained structural analogues With the end of vasopressin. Replacement of cysteine or cysteine at residue serine led to the Hexapeptide pGlu-Asn-Ser-Pro-Arg-Gly-NH2active in tests on learning laboratory animals at doses 00 times higher doses of vasopressin [7]. However, synthesis of these compounds is complex and multi-stage, because increasing the number of amino acid residues, increasing the number of stages of the synthesis.

In the last two decades were found several different types of vasopressin receptors and it is shown that the different activities implemented by the binding molecules of the ligand with different types of receptors [8, 9]. Obviously, a more narrow spectrum of activity C-terminal analogues in comparison with the natural hormone is associated with their higher selectivity with respect to the receptors of vasopressin.

The present invention is the creation of medicines with neurotropic activity.

The technical result that can be obtained by carrying out the claimed invention is to provide new compounds analogues of the C-terminal region of the vasopressin able to selectively connect with different subtypes of receptors of vasopressin and consequently with different types of neurotropic activity of the antidepressant effect, stimulating effect on the processes of memory, locomotor activity), low-toxic, suitable for introduction available intranasal method that can be used to create a nootropic drugs.

This result is achieved by creating with it Otradnoe activity of the peptide of General formula: Ac-X-Met-Pro-Arg-Gly-NH 2where X Is Met-L-Met and DL-Met.

To achieve this goal held modification of the C-terminal tetrapeptide vasopressin - replacement of Cys on the optical isomers of N-acetylation - Ac-D-Met, Ac-L-Met and Ac-DL-Met. Replacement of Cys at stereoisomers Ac-Met allows you to save important elements such patterns, as the presence of a nucleophilic sulfur atom, and the acylation of the α-amino group of methionine increases the enzymatic stability of the peptide. Theoretical conformational analysis showed significant differences stable conformations obtained Stereolab, which leads to high selectivity in binding with different subtypes of receptors of vasopressin.

Synthesis of tetrapeptide Ac-X-Met-Pro-Arg-Gly-NH2where X Is Met-L-Met and DL-Met is performed using reactions in peptide condensation dicyclohexylcarbodiimide (DCGK) or diisopropylcarbodiimide (DIPC) with the addition of oxibendazole (MBT). Dipeptide Boc-Pro-Arg produced by the method operations esters, then condense it with Amida glycine derived tripeptides with BOC-protected amino groups will unlock processing model HC1 in ethyl acetate, the reaction Pro-Arg-Gly-NH2and Na-acetylated of Stereolab methionine in the presence of DEPC and MBT receive stereoisomer peptides of General formula Ac-X-Met-Pro-Arg-Gly-NH2.

In the developed schemes of synthesis of the protection of guanidinium moiety of arginine performs the I protonation, that allows you to get a connection with a minimum number of stages of the synthesis by eliminating stages of obtaining NG-protected derivatives and removal of protective groups.

The method of synthesis of a peptide of General formula Ac-X-Met-Pro-Arg-Gly-NH2where X Is Met-L-Met and DL-Met is described in the examples. The molecular mass of the synthesized peptides identified using mass spectrometry. Mass spectra FAB recorded on a mass spectrometer LCQ FLEET ("Thermo"). The homogeneity of the compounds was checked by TLC on plates "Sorbfil" (Russia)using the following solvent mixtures as eluents: nbutanol-acetic acid-water, 4:1:1 (A); chloroform-methanol - 25% ammonia 60:45:15 (B); chloroform-methanol-25% ammonia-acetic acid 60:45:15:3 (In); ethyl acetate-pyridine-acetic acid-water 10:10:3:6 (D). Substances were detected on the chromatograms using chlorbenside samples. Specific rotation of the studied compounds were measured on spectropolarimeter J-20 "Jasco (Japan).

Example 1.

Nα-Trebuetsyasistemnye"prolyl-arginine (Boc-Pro-Arg)

To a solution of 2.15 g (10 mmol) of tert-butyloxycarbonyl-Proline and 1.26 g (11 mmol) of N-oxysuccinimide in 12 ml of fresh dioxane was added when 7°C, 2.16 g (10.5 mmol) DCGK intensive mixing of the reaction mass. Stirring is carried out for 1 hour while cooling, 3 hours at room temperature. The resulting wasp is OK DCGM filtered off, washed on the filter with 2-3 ml of dioxane. Dioxane solution of the BOC-Pro-OSu was added to a solution of 1.22 g (7 mmol) of arginine in 7 ml of water. The reaction mixture is stirred at 20°C for 4 h, after the reaction is cooled to 5°C., filtered the precipitate Boc-Pro-Arg, washed it on the filter with water, cooled to 3-5°C (2×2 ml)and then with ethyl acetate (3×3 ml), dried in a vacuum desiccator to constant weight. The output of Boc-Pro-Arg 1.85 g (71%).

TPL 154-155°C [α]D20-49°(C 1, methanol), Rf0,38 (A)0,71 (B).

Example 2.

Nα-Trebuetsyasistemnye-shed-arginyl-glycinamide hydrochloride(Boc-Pro-Arg-Gly-NH2·HCl)

A mixture of 1.11 g (3.0 mmol) of Boc-Pro-Arg and 0.33 g (3.0 mmol) of the hydrochloride of glycidamide in 7 ml of DMF (reagents pre-grind in a mortar to a fine powder) is stirred for 1 h at 20°C, cooled to 0-5°C. and added 0.45 g (3.3 mmol) MBT, then of 0.68 g (3.3 mmol) DCGK. The reaction mixture was stirred 1 h at (0-5°C) and 16 h at 20°C. the Precipitate DCGM separated by filtration, washed with 2 ml of DMF. To the United dimethylformamide solution add 25 ml of ether, after compaction of the sediment layer decanted solvent, the residue is twice periostat from methanol-ether. In the presence of impurities of the source glycinamide (TLC control) is dissolved in 3-4 ml of a mixture of ethyl acetate and methanol 1:1 and to the solution was added in small portions ethyl acetate (3-5 ml) before the formation of the OS is dka. Operation repeat, if translated into the residue of the Tripeptide contains an admixture of glycinamide. Homogeneous according to TLC residue is dried in vacuum over P2O5.

The output of Boc-Pro-Arg-Gly-NH2·HCl 1.28 g (92%). TPL 85-87°C, [α]d20- 51° (C 1, methanol), Rf0,39 (B)0,51 (G).

Example 3.

Shed-arginyl-glycinamide the dihydrochloride (V) (Pro-Arg-Gly-NH2·2HCl)

A suspension of 0.93 g (2.0 mmol) of Boc-Pro-Arg-Gly-NH2·HCl in 10 ml of 4.8 n HCl solution in ethyl acetate is stirred for 120 min, monitoring completeness of removal of the BOC-group TLC systems (A) or (G), then evaporated in vacuo of the solvent, to the residue was added 5 ml of dry ethyl acetate is added and the evaporation repeated. The residue is dissolved in 3 ml of methanol, transferred to precipitate by adding 12 ml of ether. The residue Pro-Arg-Gly-NH2·2HCl-EA is separated by filtration, washed it with ethyl acetate, ether, dried in vacuum over KOH. Get 0,94 g (96%) Pro-Arg-Gly-NH2·2HCl in the form of MES with one molecule of ethyl acetate.

[α]d20- 38° (C 1, methanol), Rf0,31 (B)0,34 (G).

Example 4.

N-Acetyl-L-methionyl-shed-arginyl-glycinamide (VI) (Ac-L-Met - Pro-Arg-GIy-NH2)

To a cooled to 3°C. to a solution of 0.49 g (1.0 mmol) Pro-Arg-Gly-NH2·2HCl-EA in 3 ml of DMF is added is 0.135 ml (1.2 mmol) of N-methyl-research, after 10 min of 0.23 g (1.2 mmol) of N-acetyl-D-methionine, 0.16 g (1.2 mmol) MBT, to 0.23 g (1.1 mmol) DCGK. The reaction mixture was stirred at 3-5°C in t the value of 1 h and 3 h at 20°C, then separate the precipitate by filtration DCGM, washed it 0.5 ml of DMF. To the United dimethylformamide solution add 15 ml of ether, after compaction of sludge decanted the supernatant, the residue is dried in vacuum over P2About5, periostat from chloroform-ether from methanol-ethyl acetate. The precipitate was separated by filtration, dried in vacuum over P2O5. Get 0,42 g (83%) of N-Ac-L-Met - Pro-Arg-Gly-NH2.

In the presence of impurities of the source compounds according to TLC, a portion of the peptide is dissolved in a minimum amount of methanol and applied on a column of silica gel L 40/100, swollen in eluent chloroform-methanol-water 10:10:1. Spend elution with use of the above solvent mixture and collect the fractions containing pure product (TLC control). The combined fractions are evaporated, the residue periostat from methanol-acetone. After drying over P2O5get clean tetrapeptide in the form of white crystalline powder. Yield N-Ac-L-Met - Pro-Arg-Gly-NH20,215 g (43%).

TPL 109-110°C, [α]d20-57° (C 1, methanol),), Rf0,64 (B)0,42 (G).

Example 5.

N-Acetyl-DL-methionyl-shed-arginyl-glycinamide (VI) (Ac-DL-Met - Pro-Arg-Gly-NH2).

N-Acetyl-DL-methionyl-shed-arginyl-glycinamide receive according to the method described in example 4 for the L-isomer of 0,49 g (1.0 mmol) Pro-Arg-Gly-NH2·2HCl-EA and 0.23 g (1.2 mmol) of N-D-methionine. The output Ac-DL-Met-Pro-Arg-Gly-NH20,275 g (55%).

TPL 109-110°C, [α]d20-40° (C 1, methanol),), Rf0,64 (B)0,42 (G).

Experiments to study the effect·of peptides on the behavioral reactions were performed on male outbred rats weighing 180±30 g of the Investigated peptides were administered intranasally in aqueous solution in a volume of 1 μl/10 g body weight for 5 min before testing in the study of orienting-exploratory behavior, levels of anxiety and depression level and every day after training session in the formulation of the conditional reaction active avoidance. Animals of the control group was administered distilled water in an equivalent amount. The drugs were administered in the following doses of 0.01 mg/kg, of 0.1, 1.0 and 10.0 mg/kg

Orienting-exploratory behavior of animals investigated in the tests open field ("bestreshma" and "stress" version) and "mink camera, the level of anxiety in the test, the elevated plus maze and light-dark chamber", the degree of depression - in test "forced swim".

The production conditions one-way active avoidance reaction was carried out for four consecutive days.

Ac-L-Met-Pro-Arg-Gly-NI-b, with intranasal injection in doses of 1.0 to 10.0 μg/kg had no effect on the orienting-exploratory behavior and anxiety level of animals. But is this tetrapeptide had a strong antidepressant effect. In the test "forced swim" its introduction has affected virtually all the analyzed indicators registered a significant increase as the duration of the first period of active swimming, and total time of active swimming, increase the total time and average length of passive navigation; the total time of immobilization and the number of periods of decline.

Thus, the replacement amino acid residue in tetrapeptide fragment molecules of vasopressin on L-Met has led to the loss of influence of the peptide on the orienting-exploratory behavior and anxiety level of animals. However, the high level of the antidepressant effect of Ac-L-Met-Pro-Arg-Gly-NH2shows, apparently, that the peptide is a selective agonist V1bR receptors of vasopressin.

Tetrapeptide with racemic methionine residue Ac-DL-Met-Pro-Arg-Gly-NH2showed a range of behavioral activity, similar to the D-isomer (patent for invention №1623166 SU, 15,02 .1994 "Neuropeptides with behavioral activity"), he encouraged the learning of animals in the test of the conditional reaction active avoidance, increased motor activity and reduced emotional reactivity. In these tests, the effective doses were 5 to 10 times less compared to the D-isomer and 2 orders of magnitude lower than that of the vases is pressin.

In addition, he, like the L-isomer had a marked antidepressant effect, which was evident at doses of 1-10 mg/kg Thus, Ac-DL-Met-Pro-Arg-Gly-NH2found properties inherent and D - and L-isomers of tetrapeptide General formula Ac-X-Met-Pro-Arg-Gly-NH2where X-Met - D-Met, L-Met and DL-Met.

Sources of information

1. Patsevich O.S, Chipens GI, S.V. Mikhailov Neurohypophyseal hormones. - Riga: Zinatne. in 1986, 282 S.

2. Walter R., Van Ree J.M., de Wied D. Modification of conditioned benavior of rats by neurohypophysial hormones and analogues // Proc. Nat. Acad. Sci USA. - 1978. V.75, N 5. - P.2493-2496.

3. J.P.H. Burbach, Leboille J.L.M. Proteolytic conversion of arginine vasopressin and oxytocin by brain synaptic membranes. Characterization of peptides formed and mechanisms of proteolysis // J. Biol. Chem. - 1983. - V.258, N 3. - P.1487-1489.

4. Valter M.P., De Wied D., Van Ree J.M. Vasopressin fragment, AVP(4-9), improves long-term and short-term memory in the hole board search task // Neuropeptides. - 1997. - V.31, N 5. - P.489-494.

5. Golubovich VP, Martinovich VP, Usenko AB and other //. Chemical pharmaceutial, 1888. No. 6. - S.675-679.

6. Martinovich VP, Slobodchikov L.K., Golubovich VP, Akhrem A.A., Titov S.A., resurrection OG Synthesis and study of biological activity of C-terminal fragments of vasopressin AVP5-9and pGlu--WUA5-9// Chemical-pharmaceutcal - 1989. No. 9. - S-1057.

7. Sato, T., Tanaka K., Teramoto T et. Al. Effect of pretraining administration of NC-1900, a vasopressin fragment analog, on memory performance in non - or CO2-amnesic mice Pharmacol. Biochem. Behav. - 2004. V.78. - P.309-317.

8. Lolait S.J., O Carrol A.M. Brownstein M.J. Molekular biology of vasopressin receptors. Ann. N.Y. Acad. Sci. - 1995 - V.771. P.23-292.

9. J.p.H. Burbach, Schoots o, Hernando F. Biochemistry of vasopressin fragments. Prog /Brain res. 1998. - Vol.119. - P.127-136/.

Peptide with neurotropic activity, of General formula: Ac-X-Met-Pro-Arg-Gly-NH2,
where X Is Met-L-Met and DL-Met.



 

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EFFECT: obtaining compounds for preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals.

16 cl, 3 tbl, 1 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmaceutical industry and represents pharmaceutical combination for treatment of cerebral circulatory insufficiency and psychodependent form of erectile dysfunction, including choline alfoscetate in amount 50-600 mg per one intake and hopantenic acid or its pharmaceutically acceptable salt in amount 20-800 mg per one intake.

EFFECT: invention ensures reduction of frequency, duration and intensity of headache, dizziness, fatigability, irritability, improvement of memory for current events and sleep, as well as increase of erectile dysfunction (ED), reduction and fixation of stable positive motivation for quality erection and full orgasm in case of psychodependent form of ED; simultaneously, due to manifestation of synergic effect, which results from the use of claimed combination, it became possible to reduce day dose of hopantenic acid or its salt from 1,5 mg to 0,5 mg.

12 cl, 4 ex, 24 tbl, 4 dwg

Peptide compounds // 2393167

FIELD: chemistry.

SUBSTANCE: invention relates to novel peptide compounds and their use in diagnostic optical visualisation techniques. More specifically, the present invention pertains to use of such peptide compounds as targeted vectors which are related to receptors associated with angiogenesis. The compounds are labelled using at least one cyanine reporter dye.

EFFECT: obtaining compounds which can be used as contrast agents in optical visualisation when diagnosing diseases related to angiogenesis.

9 cl, 5 ex

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