RU2429834C1 - Antidepressant, anxiolytic, neuroprotective and immunostimulating agent - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to application of 3-phenylglutamic acid hydrochloride as an antidepressant, anxiolytic, neuroprotective and immunostimulating agent and a based drug.

EFFECT: agent exhibits low toxicity and high activity.

2 cl, 16 tbl, 6 ex

Description

The invention relates to medicine, in particular to pharmacology, and for expanding the scope of application of derivatives of glutamic (glutamic) acid in the form of 3-phenylglutamic acid hydrochloride as an antidepressant, anxiolytic, neuroprotective and immunostimulating agent.

Current socioeconomic conditions are characterized by an abundance of stressful situations and are characterized by a high prevalence of neuropsychiatric diseases, while the proportion of borderline mental disorders accompanied by anxiety-depressive symptoms, cognitive deficits, astheno-neurotic manifestations, decreased immunity, physical and mental performance is steadily increasing. Many of the known antidepressants have insufficient clinical efficacy, slow development of a clinically significant effect, low selectivity and breadth of therapeutic effect, sufficiently high toxicity, serious side effects, which significantly limits their use in wide medical practice and narrows the scope of their possible use. In addition, many of the highly effective antidepressant drugs used, in particular tricyclics, exhibit a pronounced psycho-suppressing effect, impair attention and memory, which reduces the quality of life and limits the breadth of their use in the clinic [Mashkovsky MD Medicines M., 2008]. These trends dictate the need to search and develop new highly effective and low-toxic neuropsychotropic drugs with a wide spectrum of activity that allows pharmacological correction of the set of symptoms of neuropsychiatric diseases without polypharmacy, safe for prolonged use, including by working people.

One of the most productive ways to search for psychotropic substances is to create derivatives of natural neurotransmitters through which psychotropic drugs realize their effects. Glutamic acid is the main excitatory neurotransmitter in the central nervous system (CNS), is present in the structures of the brain, participates in the regulation of its functions, including higher integrative functions (behavior, conditioned reflex activity, emotions, memory), and also modulates the activity of the immune system. Glutamic acid itself (α-aminoglutaric acid of the general formula HOOC (CH ₂ ) ₂ (NH ₂ ) COOH) is used in medicine as a psychotropic drug and belongs to the pharmacological groups: Other neurotropic drugs; Nootropics - Trade name: Glutamic acid, (INN Glutamic acid, Glutamic acid), is available in the following dosage forms: enteric-coated tablets, coated tablets ("Tathimpharmaceuticals"), granules for oral suspension [Drug registration news. 2nd quarter of 2000. Domestic preparations. Overview. Doc. honey. Sciences Shustov EB //http://www.pharmindex.ru/navigator/reg_2_1.html]. The drug has a nootropic, anticonvulsant effect. In medical practice, glutamic acid is used in the treatment of central nervous system diseases: epilepsy (mainly small seizures with equivalents), psychoses (somatogenic, intoxication, involutional), reactive states that occur with the phenomena of exhaustion, depression, etc. [Mashkovsky MD Medicines M., 2008]. The most specific side effect of glutamic acid is the excitation of varying severity, which limits its clinical use.

The substance glutamic acid does not possess the antidepressant and anxiolytic effects proper, such pharmacological effects for glutamic acid itself have not been described.

It is known to use a glutamic acid derivative in the form of N-acetyl-alpha-glutamic acid as a component of an effective psychotropic drug with nootropic effects [RF Patent No. 2068408 from 06.24.1992]. N-acetyl-L-glutamic acid is, in particular, a part of a nootropic drug with psychostimulating activity of noclerin, for oral administration [Instructions for use of the drug "Noclerin" approved by the Pharmacological Committee of the Ministry of Health of Russia 06/14/2001]. The drug has a nootropic, cerebroprotective and psychostimulating effect [Register of Medicinal Products of the Russian Federation //http://reles.ru/cat/tradefm/Nooclerin/2/].

Contraindications: Hypersensitivity to the drug, infectious diseases of the central nervous system, fever, diseases of the blood system, psychotic conditions, severe impaired liver and kidney function, pregnancy (I trimester), lactation. The antidepressant and anxiolytic effects of noclerin are not described.

The base of N- (5-hydroxynicotinoyl) -L-glutamic acid (nooglutyl) is known, which have anti-stroke, geroprotective, nootropic and antihypoxic effects, and mono- and divalent salts of N- (5-hydroxynicotinoyl) -L-glutamic acid (general formula ( HO) C ₆ H ₅ N) (CONH) CH (COOX) (CH ₂ ) ₂ COOY, where X = Y or Na or K or CaOH), characterized by the presence of psychotropic effects (antidepressant and anxiolytic) and neuroprotective activity [RF Patent No. 2314293 dated 07/31/2006].

A glutamic acid derivative is known to be a peptide (of the general formula R NH CH (COOH) (CH ₂ ) n COX, where n = 1, 2; R = hydrogen, lower acyl or lower alkyl; X is a heteroaromatic amino acid); possessing immunomodulatory activity [RF Patent No. 2142958 from 12.25.1997]. There is also described a drug (drug) having immunomodulatory activity, containing the indicated peptide and auxiliary additives.

The pharmacological activity of phenyl-glutamic acid derivatives is not described.

Known anxiolytic drugs are benzodiazepine derivatives, in particular, diazepam, phenazepam. However, along with anxiolytic activity, they have pronounced side effects - they cause muscle relaxation, decreased muscle tone, general sedative effect, daytime drowsiness, memory impairment, and with prolonged use - addiction, drug dependence. Known cerebroprotective agent is piracetam, which has a low efficiency and side effects. Piracetam can cause sleep disturbance, increased seizure readiness, general, non-specific arousal.

Derivatives of gamma-aminobutyric acid (butanoic acid), in particular 3-phenyl-4-gamma-aminobutyric acid hydrochloride under the name Phenibut (general formula H ₂ N CH ₂ CH (C ₆ H ₆ ) CH, are widely used in medicine as tranquilizers. ₂ COOH · HCl), which has a nootropic activity that has an anxiolytic effect [Mashkovsky M.D. Medicines M., 2008]. The antidepressant activity of phenibut has not been described. Salts of 4-amino-3-phenyl-butanoic acid (general formula X · n (H ₂ N CH ₂ CH (Ph) CH ₂ COOH), where X is an acid (citric or oxalic or succinic or malic), n = 3 or 2), known for their nootropic activity [RF Patent No. 2220131 of 02.28.2002], have anxiolytic and cerebroprotective properties [RF Patent by application No. 2008152660 of 29.12.2008].

Taking into account the breadth and physiological significance of neurotransmitter amino acids, in particular glutamine derivatives. acids, the search and creation on its basis of new pharmacologically active structural analogues, with the alleged psychotropic effect and the possibility of therapeutic use, is promising.

The objective of the invention is to obtain an effective low-toxic agent based on glutamic acid, which has a pronounced antidepressant effect with a high rate of development of a clinically significant effect, anxiolytic, neuroprotective and immunostimulating effects, as well as nootropic properties, to expand the range of such agents.

The task is implemented by the proposed tool, including a derivative of glutamic acid: 3-phenylglutamic acid hydrochloride.

It was first discovered that 3 - phenylglutamic acid hydrochloride has an antidepressant, anxiolytic, neuroprotective and immunostimulating effect. The essence of the invention lies in the use as an antidepressant, anxiolytic, neuroprotective and immunostimulating agent of a known substance - 3-phenylglutamic acid hydrochloride of the general formula

At the same time, the product has a complex of biologically active properties that exceed those that are absent or absent in the starting substance, in comparison with a number of known target drugs, it exhibits:

- at a dose of 13 and 26 mg / kg, a pronounced antidepressant effect is not inferior to the action of melipramine (15 mg / kg) and significantly superior to the effect of coaxil (12.5 mg / kg) and fluoxetine (20 mg / kg);

- anxiolytic activity exceeding the activity of coaxil and afobazole (5 mg / kg) and comparable with the action of diazepam (1 mg / kg);

- moderate activating properties comparable with melipramine, neuroprotective effect not inferior to the effect of phenibut (25 mg / kg);

- at a dose of 30 mg / kg, a stimulating effect on the cellular and humoral components of the primary immune response, enhances lympho-proliferative processes in immunocompetent organs, having a pronounced immunostimulating effect.

The synthesis of 3-phenylglutamic acid hydrochloride is two-stage, involves the interaction of 1,1-imethoxycarbonyl-2-phenylethene with acetylamino-malonic ester and subsequent hydrolysis of the resulting intermediate dimethyl-2-acetylamino-2,4-dimethoxycarbonyl in dilute (1: 1) hydrochloric acid -3-phenylglutaroate [Kobzareva V.K., Deiko L.I., Vasilyeva O.S., Berestovitskaya V.M., Berkova G.A. A new method for the synthesis of 3-phenylglutamic acid // Zhokh. 1997.V. 33. Issue 8. S. 1180-1181].

An example of obtaining 3-phenylglutamic acid hydrochloride.

First stage. To a solution of sodium methylate obtained from 3.9 ml of methanol and 0.15 g (0.0065 mol) of sodium metal, 1.4 g (0.0065 mol) of diethylacetylaminomalonate are added with stirring and the mixture is allowed to stand until the precipitate is completely dissolved. Then, a solution of 1.43 g (0.0065 mol) of 1,1-dimethoxycarbonyl-2-phenylethene in 10 ml of methanol is added in portions, maintaining the temperature at 0 ÷ 5 ° C. The reaction mass is kept under stirring for one hour and poured onto ice crumbs with a calculated amount of sodium hydrochloric acid (1 ml) (pH ~ 7): The crystalline product is filtered off and 2 g (75%) of dimethyl-2-acetylamino-2 are obtained. 4-dimethoxycarbonyl-3-phenylglutaroate. Second stage. A solution of 2.46 g (0.0065 mol) of dimethyl-2-acetylamino-2,4-dimethoxycarbonyl-3-phenylglutaroate in 60 ml of diluted (1: 1) hydrochloric acid is boiled for 9 hours. The hydrolyzate is evaporated under reduced pressure. The residue is treated with acetone. The crystalline product is filtered off and 1.10 g (70%) of 3-phenylglutamic acid hydrochloride is obtained.

The synthesized 3-phenylglutamic acid hydrochloride has the following physicochemical properties. Melting point 186-188 ° C (acetone-water 1: 1). IR spectrum (KBr), ν, cm ^-1 : 1700-1720 (C = 0); 3300-2650 (NH). ¹ H NMR Spectrum, (DMSO-d ₆ ), δ, ppm: 2.68-3.15 k (CH ₂ COO); 4.08 m (CHCOO); 3.70 m (CH-Ar); 9.50 (NH ₃ ⁺ ); 7.17-7.38 (C ₆ H ₅ ): Found,%: C 50.88; 50.84; H 5.49; 5.50; N, 5.35; 5.39 C ₁₁ H ₁₄ NO ₄ Cl. Calculated,%: C 50.88; H 5.43; N, 5.39.

The acute toxicity of 3-phenylglutamic acid hydrochloride, estimated by the survival rate of white mice 24 hours after administration of the agent, was studied using two proposed routes of administration: parenteral (intraperitoneal) and enteric (intragastric). To calculate the magnitude of the toxicological index LD ₅₀ used probit survival analysis [Guide to the experimental (preclinical) study of new pharmacological substances, ed. Khabrieva R.U., 2005]. Averaged values of LD ₅₀ , mg / kg: for parenteral administration of the order of 800-900, for enteral administration of more than 3000 (the difference in LD ₅₀ values between the two routes of administration is probably due to slow or incomplete absorption during enteral administration). The results make it possible to classify 3-phenylglutamic acid hydrochloride as a low-toxic agent.

The following are examples illustrating the specific activity of 3-phenylglutamic acid hydrochloride, which has a psychotropic effect of antidepressant, anxiolytic, neuroprotective and immunostimulating effects.

To demonstrate the indicated pharmacological effectiveness of the drug, 3-phenylglutamic acid hydrochloride, established methods for detecting animal behavioral activity were used; a set of psychopharmacological experimental standard tests (techniques): "Open field" (OP); “The Elevated Cruciform Maze” (PC L); “Conditional reaction of passive avoidance” (passive avoidance reaction); "Extrapolation deliverance" (TEI); Vogel Conflict Situation (COP); "Hanging mice by the tail" (PMX); “Inevitable forced swimming” according to Porsolt (NPP) and others, taking into account the requirements of the Pharmacological Committee of the Russian Federation set forth in the “Guide to the experimental (preclinical) study of new pharmacological substances”. M .: Medicine. 2005, using statistical methods of processing (evaluating) the results of the study, which allow one to evaluate both the strength of pharmacological effectiveness and the degree of its selectivity [Haunina R.A., Lapin I.P., 1976., Voronina T.A., 1982; Gelman V.Ya., Kremenevskaya S.I., 1990; Pellow S. et al., 1985; Buresh Y., Bureshkova O., Houston D.P., 1991. Voronina T.A., Ostrovskaya R.U., 2000; Bondarenko N.A., 1992; Voronina T.A., Seredenin S.B., 2000; Porsolt R. D. et al., 1977]. The essence of this approach is a comparative analysis of the behavioral effects of the studied compounds in comparable groups of animals. We used white outbred male rats randomized by age and weight, kept under laboratory vivarium conditions for at least two weeks before the experiment, on a standard diet, with free access to water, and under natural light conditions (keeping animals corresponded to the rules of laboratory practice in conducting preclinical studies in the Russian Federation (GOST R 51000.3-96 and GOST R 51000.4-96) and Order of the Ministry of Health of Russia No. 267 dated 06/19/2003 "On approval of laboratory rules aktiki »(GLP), in compliance with the international recommendations of the European Convention for the Protection of Vertebrate Animals used for experimental studies, 1997). The experiments were carried out at the same time of day. Control animals were injected with an equivalent volume of water for injection. The values of the indicators given in the tables represent the average statistical assessment of the measurement results of the parameters taking into account the accepted levels of reliability (p <0.05; p <0.01).

Evaluation of the effectiveness of hydrochloride-3-phenylglutamic acid was carried out by comparison with the activity of the most effective drugs of similar directions of action used in clinical practice:

afobazole - anxiolytic with a slight stimulating (activating) effect, the drug has no muscle relaxant properties, a negative effect on memory and attention;

diazepam is an anxiolytic, has a calming, hypnotic, anticonvulsant, muscle relaxant and amnestic effect. Enhances the effect of sleeping pills, narcotic, antipsychotic, analgesic drugs;

Melipramine - an antidepressant, has a psychostimulating effect;

tianeptine (coaxyl) antidepressant, occupies an intermediate position between sedative and stimulating antidepressants, does not adversely affect memory, sleep and ability to concentrate;

Phenibut is a drug with nootropic and anxiolytic effects, has tranquilizing activity, reduces tension, anxiety, fear, improves sleep. It lengthens and enhances the effect of sleeping pills, drugs, antipsychotics;

phenotropil - a nootropic drug with a neuroprotective, anticonvulsant, anxiolytic and antidepressant effect;

fluoxitin (Prozac) - an antidepressant, improves mood, reduces feelings of fear and tension, eliminates dysphoria, does not cause a sedative effect.

Antidepressant effect

Example 1. The studied tool: 3-phenylglutamic acid hydrochloride (hereinafter referred to as 3-FHA hydrochloride, or as (tested, proposed) tool), was administered to animals intraperitoneally, once at a dose of 1/10 of the molecular weight (according to [Guidelines for the experimental (preclinical) study of new pharmacological substances, under the editorship of Khabriev R.U., 2005]), that is, 26 mg / kg, as well as a twofold decrease (13 mg / kg) and an increase (52 mg / kg ) and a dose of 80 mg / kg (1/10 of the LD component ₅₀ which is considered to be the maxim noy potentially safe). The test drug, as well as the comparison drugs, were diluted in 2% starch mucus, in an equivalent volume, immediately before use, and were administered once 45 minutes before the tests and a 14-day course (with the last injection 45 minutes before the tests) through the probe. Control animals received a similar solution of starch mucus in an equivalent volume according to a similar scheme. The results are presented in Tables 1-3, 3-FGC Hydrochloride at a dose of 26 mg / kg when administered once to animals, statistically significantly increases the latent period before the development of immobility and reduces the total time of immobilization in animals; also statistically significantly increases the number of jumps in animals, which indicates a pronounced antidepressant effect. With a course of administration, 3-FGK hydrochloride statistically significantly increases the latent period before the development of immobility and reduces the total time of immobilization in animals, as well as increases the number of jumps, which indicates the antidepressant effect of the drug. Comparison of the antidepressant activity of the agent and comparison preparations of a similar purpose showed that in the forced swimming test, the agent, as well as the drugs, glutafen, coaxil, fluoxetine and melipramine, have a pronounced antidepressant effect: the latency period of immobilization, the number of jumps and the duration of active swimming were statistically significantly increased, and also significantly reduced the duration of immobilization in animals. At the same time, according to the effect on the performance of the NPP test, the agent is statistically significantly superior to coxil and fluoxetine and is not inferior to melipramine. The agent is statistically significantly superior in terms of the severity of the antidepressant effect to such antidepressants as a serotonin reuptake inhibitor - fluoxetine (Prozac), and a tricyclic antidepressant that enhances serotonin neuronal uptake - tianeptin (coaxyl). In addition, unlike these drugs, it does not cause sedation and impaired reaction rate, but rather has an activating effect and the ability to increase the rate of indicative reactions.

Conclusion Hydrochloride. 3-phenylglutamic acid exhibits a pronounced antidepressant activity both in the course and in a single application, most pronounced in doses of 13 and 26 mg / kg. The antidepressant effect of the proposed drug (26 mg / kg) significantly exceeds the effect of coaxil (12.5 mg / kg) and fluoxetine (20 mg / kg), not inferior to the action of melipramine (15 mg / kg). However, unlike the latter, the tool does not violate memory and attention, but, on the contrary, (as follows from the following examples), exhibits nootropic properties (in conditions of impaired functions of stressor and convulsive genesis it contributes to memory preservation). In addition, unlike melipramine, the drug has a wider spectrum of psychotropic action, which also includes a pronounced anxiolytic effect and neuroprotective activity, which expands the scope of its possible clinical use.

Anxiolytic effect

Example 2. The dosages studied by the agent were administered to animals in the same way as in Example 1. Specific tests of the classical anxiety model PKL and CS (Vogel) were applied. The results are presented in table 4-5. At doses of 26 and 52 mg / kg, the agent significantly increased the length of stay of rats in the bright arms of the labyrinth, the number of exits in them and the number of hanging from them, which is a pronounced manifestation of anxiolytic activity. Moreover, in all doses used, the agent statistically significantly increased the number of exits into open arms and the total motor activity (the number of transitions between arms) in animals, which indicates that it has an activating effect in these doses. At doses of 26, 52, and 80 mg / kg, the substance significantly reduced the latent period of rats' exit from the central zone, which can be associated with both its activating effect and increased locomotor activity, as well as with an increase in the rate of orientational reactions. The agent at a dose of 13 mg / kg did not have a similar effect - it did not affect the time spent by the animals in the central zone. Thus, in the PCL test, a tool for influencing the behavior of animals in a wide range of doses from 13 to 52 mg / kg exhibits a pronounced anxiolytic effect. In the range of doses from 26 to 80 mg / kg, the product accelerates indicative reactions in animals. In all doses used, the product stimulates motor activity in animals, exhibiting an activating effect. In the KS test (Vogel), it was found that at doses of 13 and 26 mg / kg, the agent significantly reduced the latent period of the first punishable water intake from the drinking bowl, in the dose range from 26 to 80 mg / kg, the number of punished attempts to quench thirst was statistically significantly increased, showing obvious anxiolytic properties. In the PCL test, the agent increased the number of animals entering open arms, the number of hanging from them, and, according to the influence on these indicators, its effect is comparable to that of diazepam and afobazole, however, the time spent in open arms increased slightly, which can be explained by a higher locomotor activity in animals treated with this drug, its activating effect. The latent period of animals' exit from the center, which characterizes the rate of orientational reactions, decreased statistically significantly under the influence of the drug and, to a lesser extent, afobazole and coaxil. The motor activity in animals (total, the number of transitions between the arms of the labyrinth) significantly increased under the influence of both the studied drug and glutafen, afobazole and melipramine, which characterizes their activating effect and statistically significantly decreased under the action of diazepam, due to its sedative effect. Thus, by the effect of the agent on the behavior of animals in the PCL test, it can be concluded that anxiolytic properties are combined with an activating effect. In the test KS (according to Vogel), the anxiolytic properties of the drug were also confirmed. In animals treated with the drug, there is a statistically significant, significantly less latent period of the first punishable taking of water from the drinking bowl and a greater number of punishable attempts to quench thirst. Moreover, the studied agent showed an anxiolytic effect comparable with the effect of diazepam and statistically significantly superior to the effects of afobazole.

Conclusion 3-Phenylglutamic acid hydrochloride has an anxiolytic effect both in the course and in a single dose, most pronounced at a dose of 26 mg / kg, as well as moderate activating properties comparable with the similar effect of melipramine (15 mg / kg). The anxiolytic activity of the proposed drug exceeds the activity of coaxil (12 mg / kg) and afobazole (5 mg / kg) and is comparable to the effect of diazepam (1 mg / kg).

Neuroprotective effect

The neuroprotective effect of the drug was investigated in conditions of impaired functional activity of the central nervous system of stress and convulsive origin. Acute emotional pain stress was modeled by suspending animals from the dorsal cervical skin fold at a height of 1.5 m from the floor for 24 hours (the duration of suspension was selected on the basis of literature data indicating that a detailed picture of the general maladaptation process is achieved during this time interval [ Ostrovsky O.V., Dudchenko G.P., 1985]). To prevent injury to animals, rubber tips were put on jaws of clamps. Phenibut neuroprotectors (50 mg / kg) and phenotropil (50 mg / kg), which have a pronounced stress-protective effect [Adaptogenic effect of nootropic drugs under experimental stress in animals, were used as comparison preparations. Akhapkina V.I. // Well .: Farmateka, No. 14, 2005. http://medi.ru/doc/310110.htm]. Groups of animals were formed: control - control 1 (intact animals that were not subjected to stress during the experiments) and control 2 (control animals subjected to stress); Subjects receiving the test agent and reference drugs subjected to stress (3-FGK hydrochloride + stress), (phenibut + stress), (phenotropil + stress). The studied drug, comparison preparations, and a 2% starch mucus solution were administered to the control animals once orally prophylactically 45 minutes before stressing. The studied agent, comparison preparations, and physiological saline to the control animals were administered once prophylactically orally 45 minutes before stressing. Modeling of chronic stress by deprivation of the paradoxical phase of sleep [T. Voronina et al., 2005; Kovalzon V.M., 2006; Jouvet et al, 1964] was carried out in a bathtub filled with water, on the surface of which there were platforms measuring 6.0 × 6.0 cm, projecting 2 cm above the water level. Animals were placed on the platforms for 24 hours with preliminary administration of the test substances. After the indicated time interval, the animals were returned to individual cages for 24 hours with free access to water and food, the cycle was repeated 5 times, the total duration of stress was 10 days. Comparison preparations, their doses and route of administration were similar to those used in modeling acute stress. The agent, the comparison preparations, the solution of 2% starch mucus to the control animals were administered prophylactically 45 minutes before each placement on the islets. A functional assessment of the effect on the severity of neuropsychiatric stress-related disorders in animals was carried out in standard psychopharmacological tests of OP, PCL, passive avoidance reaction, and TEI, which allow assessing the state of spontaneous motor, orientational-research activity, the level of emotional response, as well as cognitive functions. The tests of OP and PCL were performed in the interval 60-120 min after stressing the animals. Passive avoidance reaction test was performed in two stages. The first test was conducted to develop the skill of passive avoidance and the formation of groups of animals with similar latency indicators of the first entry into the dark compartment and the number of visits, that is, similar learning parameters. Reproduction in the passive avoidance reaction test was carried out within 60-120 min after stress to study the preservation of memory function. To confirm the presence of antiamnestic activity of the studied substances, the TEI test was used (training to solve the extrapolation problem before stressing and reproducing the skill in the interval 60-120 min after the end of stressing). Since under stress there is an activation of lipid peroxidation (LP), which leads to damage to cell membranes and a decrease in their resistance to damaging agents [Kukley M.L. et al., 1994; Pertsov S.S., 2004], the analysis of the effect on the resistance of red blood cells by the method of acid hemolysis [Terskov I.A. et al., 1957]. To measure the optical density of erythrocyte suspension, a KFK-2 photocolorimeter (red filter) was used. A morphological assessment of the effect of 3-FHA hydrochloride and comparison drugs on morphosomatic manifestations of stress was performed by determining the severity of the “stress triad” (adrenal hypertrophy, involution of lymphoid organs, ulceration of the gastric mucosa). Rats were euthanized by the administration of sodium thiopental at a dose of 80 mg / kg, then they were opened, after which the adrenal glands, thymus, spleen and stomach were removed. On a torsion balance, adrenal gland, thymus and spleen were weighed to determine the relative weight in mg / 100 g of the weight of the animal. The stomach was opened according to great curvature and washed, the number of erosions and ulcers on the mucous membrane was calculated and the degree of its damage was determined (on the Pertsova scale S.S., 1995).

Example 3. The study of neuroprotective effects on the model of acute stress. The results are presented in table. 6-9. Acute emotional pain stress caused control group 2 (stressed) rats, compared to control group 1 (non-stressed) animals, a pronounced disorganization of spontaneous individual behavior: in the OP test, disinhibition of motor and orientational-research activity, the latter indicator increased, mainly , due to the increase in the number of racks, which characterizes the increase in the level of anxiety (Waldman A.V., 1987). The PCL test also showed an increase in locomotor activity in stressed rats of control group 2, the latent period of exit from the center (the animals spent more time making decisions), which indicates a decrease in the rate of orientational reactions (deterioration in cognitive function), the preference for dark sleeves over light ones (manifestation anxiety-phobic state). Under the influence of stress in control group 2, a decrease in the resistance of red blood cells to acid hemolysis was noted. In the passive avoidance reaction and TEI tests, the depressing effect of acute stress on cognitive and mnemonic functions was noted, which was manifested in a decrease in the latency period of the first entry into the dark compartment and an increase in the number of entries in it in the passive avoidance reaction, an increase in the latent diving period, in the TEI test at the stage of post-stress reproduction of reflexes avoidance in rats of group control 2 compared with group control 1. In addition, in animals of group control 2 (stressed animals), the characteristic stressful triad Selje was revealed: hyper rofiya adrenal glands, spleen and thymus involution, erosive and ulcerative lesions of the mucous membrane of the stomach). The listed changes in the neuropsychiatric and morphosomatic status, as well as the stability of the erythrocyte membranes were statistically significant when comparing the control 2 and control 1 groups. In the PKL test, the tested drug (26 mg / kg), comparable with phenibut and phenotropil to increase the time spent in animals in the open labyrinth arms compared with the control group (in stress), it helped to reduce the severity of anxiety and fear caused by emotional pain stress. In addition, the agent, equally with phenotropil, statistically significantly reduced the duration of the latent period of exit from the center in the PKL test, i.e. increased the rate of indicative reactions in animals compared with the stress control, and exceeded phenibut in its effect on this indicator. The restoration of the rate of indicative reactions (one of the components of cognitive function) under the action of the drug, phenibut and phenotropil indicates an improvement in cognitive function in animals in the post-stress period, being a component of the nootropic and neuroprotective effects of these substances. In the passive avoidance reaction test, the drug, like phenibut (50 mg / kg) and phenotropil (50 mg / kg), statistically significantly reduced the number of animals in the group that entered the dark compartment and increased the latent period of the first entry into it, that is, they suppressed the amnesic effect of acute stress and contributed to the improvement of cognitive functions: showing nootropic and neuroprotective properties. In the TEI test, the agent is comparable to phenibut and, as in the passive avoidance reaction test, helped to preserve memory in animals subjected to acute stress, that is, showed nootropic and neuroprotective properties. When studying the effect on morphosomatic status, the studied agent significantly increased the mass of lymphoid organs (thymus and spleen) compared with the control group (in stress), thereby indirectly increasing the body's immune defense, a decrease in which is provoked by stress. When modeling the acid hemolysis of erythrocytes in stressed animals treated with the drug, as well as phenibut and phenotropil, compared with the control group indicator (in stress), a significantly longer time to complete destruction of red blood cells and lower hemolysis intensity were noted, which indicates less damage to their cellular membranes under stress-induced intensification of LP. The indicated effect of the agent is comparable in severity with the effect of phenibut and phenotropil, indicating the presence of antioxidant properties.

Example 4. The study of neuroprotective effects on the model of chronic stress. The results are presented in table.10-13. Chronic stress caused the control group 2 neuropsychiatric and morphosomatic disorders similar to those observed in acute stress, but more pronounced. The test tool slightly increased the length of time the animals were in open arms and slightly decreased the latent period of exit from the center of the maze, compared with control group 2, whereas after modeling acute stress under the action of the tool, a more pronounced improvement in these indicators was noted. Such differences in the effect of a substance on a specified indicator when modeling acute and chronic stress speaks in favor of a stronger damaging effect of the latter (for selected models). In the passive avoidance reaction test in chronically stressed rats treated with the drug, as well as comparison drugs, there was a decrease in the severity of post-stress cognitive impairment: an increase in the latent period of the first entry into the dark compartment and a decrease in the number of animals in the group who visited it. The studied drug, according to the severity of the nootropic effect in the passive avoidance reaction test under chronic stress, was not inferior to the reference drug phenibut, but was less active than phenotropil. In the TEI test during the reproduction of the skill, after chronic stress in animals treated with the positive control drug and preparations, a decrease in the time spent on solving the extrapolation problem was noted compared with stress control 2. Thus, from the results of the passive avoidance reaction and TEI tests, it follows that the drug (26 mg / kg) helps preserve memory in animals exposed to chronic stress, that is, it exhibits nootropic and neuroprotective properties. The protective effect of the drug on the cognitive function of animals exposed to chronic stress was not inferior to phenibut (50 mg / kg), and phenotropyl (50 mg / kg) in some respects. In addition to the indicated, after chronic stress in animals of the control group (in stress), a statistically significant decrease in body weight was noted. The drug, like phenibut and phenotropil, prevented a stress-induced decrease in the body weight of animals, compared to control group 2, but to a lesser extent than in acute stress. The tool also prevented the stress-induced intensification of acid hemolysis of red blood cells: comparable with phenibut and phenotropyl, it decreased the intensity and increased the duration of the destruction of red blood cells.

Example 5. The study of neuroprotective action in conditions of impaired functional activity of the central nervous system caused by convulsive syndrome. The dysfunction of the central nervous system in animals was caused by modeling a generalized seizure by administering picrotoxin subcutaneously to the cervical spine at a dose of 2.5 mg / kg [Voronina TA, Nerobkova TN, 2000]. Groups of animals were formed: control - control 3 (intact animals that were not subjected to simulations of seizures during the experiments) and control 4 (control animals that caused a seizure); Subjects receiving the test drug, simulated seizures, (3-FGK hydrochloride + seizures). The severity of neuropsychiatric disorders in animals due to generalized convulsive syndrome was tested in standard psychopharmacological tests of OP and passive avoidance reaction. The OP test was performed in the interval 60-120 min after the termination of seizures in animals. Passive avoidance reaction test was performed in two stages. The first test was carried out 24 hours before the simulation of the convulsive syndrome in order to develop passive avoidance skills and to form groups of animals with similar latency of the first entry into the dark compartment and the number of visits, i.e., similar learning parameters. Reproduction was carried out within 60-120 minutes after seizures to study the preservation of memory function. The test substance was administered to rats once orally at a dose of 26 mg / kg 45 minutes prior to administration of picrotoxin. Control animals received saline in an equivalent volume. The results are presented in table.14. The tool reduced the severity of post-convulsive changes in spontaneous behavior and mnemonic function, which was manifested in a statistically significant increase in motor and orientation-research activity (in the OP test) in animals subjected to generalized seizures and a decrease in the number of animals in the group with passive avoidance reflex amnesia (in the passive avoidance test) , in comparison with the indicators of the control group 2. Thus, it follows that under conditions of generalized seizures, the agent exhibits neuroprotective properties.

Conclusion 3-Phenylglutamic acid hydrochloride (at a dose of 26 mg / kg) has a pronounced nootropic and neuroprotective effect; which are manifested in a decrease, in comparison with the group of stressed control, the severity of post-stress and post-convulsive neuropsychiatric disorders: the best state of cognitive functions; a higher rate of indicative reactions and the elimination of anxiety. In addition, the proposed tool helps to reduce the severity of morphosomatic disorders caused by both acute and chronic stress: it prevents the involution of lymphoid organs - the thymus and spleen, which indicates its antistress and neuroprotective effect. In addition to the above, the tool helps to stabilize erythrocyte membranes under stress-induced activation of lipid peroxidation (LP), which is one of the mechanisms of its neuroprotective effect under stress.

Immunotropic effect

Example 6. The study of the effect of funds on the cellular and humoral link of the primary immune response. In this series, animals were immunized with a corpuscular antigen - sheep erythrocytes. Animals of the experimental group received intraperitoneally administered 3-phenylglutamic acid hydrochloride at a dose of 30 mg / kg (3 days: during immunization, as well as with an interval of 1 day, before and after immunization). The results are presented in table.15. It has been established that the tool promotes the activation of the cellular component of immunogenesis: the delayed-action hypersensitivity reaction index (RGST) in experimental animals exceeds this indicator in the control group by more than 20%. Evaluation of humoral, immunoreactivity showed that under the action of the agent, the intensity of antibody formation increases: the antibody titer in the passive temagglutination reaction (RPHA) is more than 15% higher than the background values in the control. Thus, the results obtained indicate a stimulating effect of the agents on cellular and humoral immunoreactivity, which indicates the presence of immunotropic properties.

Example 7. The results of a study of the effect of the drug on the mass and cellularity of the animal immunocompetent organs. Animals of the experimental group received the drug intraperitoneally at a dose of 30 mg / kg (3 days). The animals were removed from the experiment one day after the last injection of the studied substance. The results are presented in table.16. It was found that the tool causes changes in the morphometric parameters of the organs of the immune system. There is a significant increase in the mass of the spleen and the number of splenocytes and thymocytes in comparison with animals in the control group. Thus, the tool enhances lymphoproliferative processes in immunocompetent organs, which also indicates the presence of immunotropic properties.

Conclusion Hydrochloride of 3-phenylglutamic acid (at a dose of 30 mg / kg) stimulates the cellular and humoral link of the primary immune response, and also enhances lymphoproliferative processes in immunocompetent organs, having a pronounced immunostimulating effect. The combination of properties identified in the proposed tool, in combination with low toxicity, indicates the presence of an immunostimulating effect, make them promising for the treatment of diseases of the central nervous system.

so

Comparative experimental study of the properties of 3-phenylglutamic acid hydrochloride of the general formula

revealed that the drug exhibits antidepressant, anxiolytic, neuroprotective and immunostimulating activity.

The hydrochloride of 3-phenylglutamic acid, having an anxiolytic effect not inferior to the action of diazepam, differs from the latter in the absence of a hypnosedative effect, a negative effect on memory and cognitive functions, as well as the presence of a pronounced antidepressant effect in the spectrum of pharmacological activity. The proposed tool is statistically significantly superior in anxiolytic activity to coaxil and afobazole, differs from them in a wider spectrum of pharmacological activity, including pronounced antidepressant, anxiolytic and neuroprotective effects, as well as nootropic properties. The tool compares favorably with the known analogues in the spectrum of therapeutic action by a combination of pronounced antidepressant and anxiolytic effects with a neuroprotective and immunostimulating effect, activating and nootropic properties, opening for it its own niche of therapeutic use in certain groups of patients with anxiety-depressive and astheno-depressive disorders. An important advantage of this drug over other antidepressants is its ability to exert a clinically significant effect after a single use, while most known antidepressants require a course (at least two-week use) to develop the effect. In addition, this tool, unlike a number of antidepressants used (in particular, tricyclics), does not violate memory, attention, which suggests the possibility of its use by working people.

The proposed tool compares favorably with most known anxiolytics, primarily the benzodiazepine series, in the absence of a hypnosative effect, a negative effect on cognitive and mnemonic function and, as a result, has potential suitability for use by people working in jobs requiring a high concentration of attention.

Possible indications for use:

- complex therapy of anxiety and depression, accompanied by lethargy, lethargy;

- various types of asthenic conditions with lethargy, lethargy, apathy, drowsiness, physical inactivity, depressed mood;

- astheno-neurotic conditions and neurosis-like disorders, including in case of somatic diseases, after traumatic brain injuries.

Medicines based on 3-phenylglutamic acid hydrochloride, depending on the pharmaceutically acceptable carrier chosen, in an effective dose may be liquid or solid dosage forms, for example, injection solutions; various tablets and granules; capsules; suppositories.

Table 1 Indicators of animal behavioral activity under the conditions of the PMX technique with a single injection of the drug in a screening dose of 26 mg / kg The name of indicators The drug and the values of the indicators 3-FGK hydrochloride saline (control) Latent period of immobilization, sec 69.6 55.1 The total duration of immobilization, sec 136 174

Table 1.1 Indicators of behavioral activity of animals in the conditions of the NPP technique with a single injection of the drug in a screening dose of 26 mg / kg The name of indicators The drug and the values of the indicators 3-FGK hydrochloride saline (control) Latent period of immobilization, sec 43,4 17.5 The total duration of immobilization, sec 10,4 69 Number of jumps - active attempts to avoid an aversive environment 24.1 fifteen. The total duration of active swimming, sec 163 106

table 2 Indicators of animal behavioral activity under the conditions of NPP methodology depending on the dose of the drug, (+) - increase, (-) - decrease The name of indicators The values of the indicators, in %% relative to the control, depending on the dose (mg / kg) 13 26 52 80 The latent period of immobilization +65.0 +50.0 +61.0 0,0 The total duration of immobilization -77.4 -74.4 -56.9 +91.3 Number of jumps - active attempts to avoid an aversive environment +77.1 +58.7 +27.5 +6.4 Total duration of active swimming +123 +112 +64.4 +11.1

Table 3 Indicators of behavioral activity of animals in the conditions of the NPP methodology when using means and preparations of comparison (14-day course introduction) The name of indicators Name and dose (mg / kg) of the drug, indicator values hydrochloride 3-FGK, 26 coaxil, 12.5 fluoxetine, 20 melipramine, 15 afobazole, 10 diazepam 1 saline (control) Latent period of immobilization, sec 57.6 41.5 39.9 51.1 28.9 22.4 26.5 The total duration of immobilization, sec 22.1 36.8 43.9 31 65.5 86.5 69,4 Number of jumps - active attempts to avoid an aversive environment 25.5 22.4 18.6 24.5 15.1 9.9 12,4 The total duration of active swimming, sec 160 137 131 154 86 65 76

Table 4 Indicators of animal behavioral activity under the conditions of the PCL method depending on the dose of the drug, (+) - increase, (-) - decrease The name of indicators The values of the indicators, in %% relative to the control, depending on the dose (mg / kg) 13 26 52 80 Number of animals entering open sleeves +77.8 +66.7 +33.3 +12.2 Time spent in open sleeves, sec -3.4 +21.6 +19.3 +94.3 Time spent in the central zone, sec -8.7 +57.3 +59.2 +47.6 Number of uprights in open sleeves +35 +41.1 +21.2 +10.3 Number of hangings from open sleeves +22.4 +38.2 +25.5 +5.9 Locomotor activity +54.8 +42.8 +48.1 +33.3

Table 4.1 Indicators of behavioral activity of animals under the conditions of the KS method, depending on the dose of the drug, (+) - increase, (-) - decrease The name of indicators The values of the indicators, in %% relative to the control, depending on the dose (mg / kg) 13 26 52 80 Latent period of the first punished approach to the drinker, sec -50.7 -67.1 +6.6 +36.9 Number of punishable drinking approaches -14.3 +133 +57.1 +38.1

Table 5 Indicators of behavioral activity of animals under the conditions of the PCL technique when using means and preparations of comparison The name of indicators Name and dose (mg / kg) of the drug, indicator values hydrochloride 3-FGK, 26 coaxil, 12.5 fluoxetine, 20 melipramine, 15 afobazole, 10 diazepam 1 saline (control) Number of animals entering open sleeves 2,4 1,6 2 1.9 2.5 1,5 1.4 Time spent in open sleeves, sec 29.1 33.9 28.9 23.9 34.5 40,4 25.6 Latent period of exit from the central zone, sec 11.1 12,4 19.6 15.1 12.6 32.1 18,4 Number of hangings from open sleeves 3.9 2.9 2,8 2.5 3.6 3.8 2.6 Locomotor activity 6.4 4.4 5.2 6.1 6.5 3,5 4.4

Table 5.1 Indicators of behavioral activity of animals under the conditions of the KS method using the means and preparations The name of indicators Name and dose (mg / kg) of the drug, indicator values hydrochloride 3-FGK, 26 coaxil, 12.5 fluoxetine, 20 melipramine, 15 afobazole, 10 diazepam 1 saline (control) Latent period of the punished approach to the drinker, sec 65.6 85,2 91.8 108.6 74.5 59.9 112.4 Number of punishable drinking approaches 3,1 2 2.1 1.4 2,4 3.4 1,5

Table 6 Indicators of behavioral activity of animals under the conditions of the methodology of OP when using means and preparations of comparison after acute emotional and pain stress The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Physical activity (number of crossed squares) 31.6 24.6 20,4 32.8 17.4 Vertical racks 5,6 3 2 four one Approximate research activity (the sum of racks and peeping in holes) 7 5.3 4.3 6.4 2

Table 6.1 Indicators of behavioral activity of animals under the conditions of the PCL technique when using means and preparations of comparison after acute emotional and pain stress The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Time spent in open sleeves, sec 27.5 21,4 24.6 15.7 thirty Time spent in the central zone, sec 17.5 28.1 11.8 41 22

Table 7 Indicators of animal behavioral activity under the conditions of passive avoidance reaction (influence on cognitive and mnemonic functions) when using means and preparations of comparison after acute emotional and pain stress The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Latent period of entry into the dark compartment, sec 154 160 175 136 180 Animals with amnesia,% fifty fifty 37.5 75 0

Table 7.1 Indicators of behavioral activity of animals under the conditions of the TEI methodology (effect on cognitive and mnemonic functions) when using means and preparations of comparison after acute emotional and pain stress The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Latent diving period, sec 35.5 31.1 22.4 84.1 17 Animals that did not solve the problem in the group,% 0 0 0 25 0

Table 8 The effect of a single prophylactic administration of the drug on the severity of stress-related morphosomatic disorders in animals subjected to acute emotional pain stress The ratio (coefficient) of the mass of the organ to the mass of the animal The name of the means and preparations of comparison, the value of the indicators, mg / 100 g 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 adrenal glands 28.7 28.6 25.1 29.6 19,4 thymus 77.3 76 78.5 61.7 82,2 spleen 279 277 274 200 312

Table 9 The effect of the drug on indicators of acid hemolysis of red blood cells in animals subjected to acute emotional pain stress Acid hemolysis of red blood cells in time, sec The name of the means and preparations of comparison, the value of the indicator,% (at E _n -E ₀ = 100%) 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 0 3.19 1.92 0.72 1.49 1.77 thirty 3.35 2.07 1.36 2.73 2.05 60 4.74 5.04 2.94 6.45 2.07 90 6.01 9.68 4.24 25.5 2.12 120 7.39 16.8 7.92 32.1 2.47 150 11.8 22.0 14.6 24.2 2.93 180 15.6 22.4 20.1 5.42 3.79 210 16,4 9.01 19.8 1,57 4.91 240 12.7 5.57 12.8 1.05 7.24 270 8.56 2.22 7.88 0 11.2 300 3.78 1.96 4.21 11.8 330 2.78 1.41 2.29 11.8 360 1.77 0 1.87 9.79 390 1.49 0 7.60 420 1,02 5.83 450 0 5.17 480 3.83 510 2.62 540 1,02 570 1,02 600 0

Table 10 Indicators of behavioral activity of animals under the conditions of the methodology of OP when using means and preparations of comparison after chronic stress depriving the paradoxical phase of sleep The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Physical activity (number of crossed squares) 48.5 52.7 27,2 41.5 24 Vertical racks 5.3 6 one 4.2 1,2 Approximate research activity (the sum of racks and peeping in holes) 6.5 6.3 1.3 4,5 1.7

Table 10.1 Indicators of behavioral activity of animals under the conditions of the PCL technique when using means and comparison preparations after chronic stress of deprivation of the paradoxical phase of sleep The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Time spent in open sleeves, sec 19.7 22.5 23.3 15,2 28.3 Time spent in the central zone, sec 15,5 11.7 10.3 18.3 10.5

Table 11 Indicators of behavioral activity of animals in terms of passive avoidance reaction (effect on cognitive and mnemonic functions) when using means and preparations of comparison after chronic stress depriving the paradoxical phase of sleep The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Latent period of the first entry into the dark compartment, sec 154 160 175 136 180 Animals with amnesia in the group,% fifty fifty 37.5 75 0

Table 11.1 Indicators of behavioral activity of animals in the conditions of the TEI methodology (effect on cognitive and mnemonic functions) when using means and preparations of comparison after chronic stress of deprivation of the paradoxical phase of sleep The name of indicators The name of the means and preparations of comparison, the value of indicators 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 Latent diving period, sec 45.4 22.1 34.1 84.5 17 Animals that did not solve the problem in the group,% 0 0 0 12.5 0

Table 12 The effect of a single prophylactic administration of the drug on the severity of stress-related morphosomatic disorders in animals exposed to chronic stress depriving the paradoxical phase of sleep The ratio (coefficient) of the mass of the organ to the mass of the animal The name of the means and preparations of comparison, the value of the indicators, mg / 100 g 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 adrenal glands 19.6 18.8 18.8 23.7 16.1 thymus 71.2 66.1 69.2 55.2 74 spleen 277 261 289 215 327

Table 13 The effect of the drug on the indicators of acid hemolysis of red blood cells in animals subjected to acute emotional pain stress, chronic stress of deprivation of the paradoxical phase of sleep Acid hemolysis of red blood cells in time, sec The name of the means and preparations of comparison, the value of the indicator,% (at E _n -E ₀ = 100%) 3-FGK hydrochloride phenibut phenotropil Control 2 Control 1 0 5.16 8.89 6.24 1.18 1,04 thirty 5.05 7.36 7.85 1.94 0.80 60 4.89 7.53 7.72 2.03 1.27 90 5.61 9.15 8.03 2.48 0.92 120 6.14 8.78 8.26 4.66 1.27 150 6.59 8.40 9.53 17.4 1,54 180 7.57 8.30 12.6 33,2 3.06 210 10.5 9.20 16.8 36.1 6.98 240 14,4 13,2 20,4 35.3 11.8 270 17.5 14.7 21,2 29.3 14.0 300 17.1 16.7 19.8 23.6 9.82 330 14.7 17.4 16.7 14.8 5.91 360 10.3 14.6 11.1 5.87 4.34 390 7.26 9.05 5.84 2.70 4.05 420 5.41 6.01 4.42 2.75 3.96 450 5.25 5.28 3.75 2.89 3.27 480 5.21 5.89 3.63 3.03 3.18 510 2.79 5.68 3.72 0 2.89 540 2.94 4.93 4.68 2,34 570 0 1.79 4.68 2.20 600 0 0 2.07

Table 14 The effect of the drug on the severity of neuropsychiatric disorders caused by generalized convulsive syndrome Name of indicator and methodology The value of indicators 3-FGK hydrochloride Control 4 Control 3 Physical activity in the test OP 26.2 17.4. 41.1 Approximate research activity in the test OP 6.7 3.3 10.1 Amnesia,%, in passive avoidance reaction test 10 71 0

Table 15 The results of a study of the effect of the drug on the cellular and humoral link of the primary immune response to animal red blood cells The name of indicators The drug and the values of the indicators 3-FGK hydrochloride saline (control) Delayed Hypersensitivity Reaction Index (RGZT),% 12,4 10 Passive hemagglutination reaction titer (RIGA), log 1,6 1.4

Table 16 The results of a study of the effect of the drug on the mass and cellularity of immunocompetent organs The name of indicators The drug and the values of the indicators 3-FGK hydrochloride saline (control) The mass of the spleen, mg 143 104 The number of nucleated cells in 1 mg of spleen, × 10 ⁵ 10,4 2,4 Thymus mass, mg 44.8 38,4 The number of nucleated cells in 1 mg of thymus, × 10 ⁴ 3,7 2,3

Claims (2)

1. The use of 3-phenylglutamic acid hydrochloride of the general formula

as an antidepressant, anxiolytic, neuroprotective and immunostimulating agent. 2. A medicine comprising an active substance and pharmaceutically acceptable carriers and additives, characterized in that as an active substance it contains the hydrochloride according to claim 1 in an effective dose and has an antidepressant, anxiolytic, neuroprotective and immunostimulating effect.