Introduction. Behavioral methods on laboratory animals are recognized as the main approach in studying the activity of potential psychotropic drugs and allow us to evaluate the main effects of new compounds, increase the possibility of predicting a successful outcome of future clinical trials.Text. This review article analyzes the main modern behavioral models in rodents that are widely used for screening and studying the pharmacological activity of potential psychotropic drugs. The advantages and disadvantages of each test are highlighted and complexes of behavioral methods are demonstrated that most conclusively confirm the reproducibility of the results obtained in clinical trials. The description and evaluation of behavioral methods that characterize the state of anxiety, which are used to screen for new compounds with anxiolytic activity (tests «Open field», «Dark-light chamber», «Elevated plus maze», «Sequence of rays»). The range of tests used to study cognitive functions and memory processes is widely presented (various mazes – T-shaped, U-shaped, radial maze, Barnes maze, E-maze; water mazes – Morris, T-maze) with a description of a comparative analysis and necessary conditions that ensure the reliability of information. An important direction in the field of behavioral pharmacology is the modeling of violations of social behavior and the study of approaches for its correction – the main methods necessary for the study of social behavior are presented in the review by the tests «Three-chamber social test», «Open field» extended test, etc.Conclusion. Behavioral pharmacology dictates the need for close interaction between preclinical and clinical stages of research in the framework of the development of translational medicine and the development of approaches that provide evidence for the reproducibility of the results obtained in clinical trials. It is also necessary to improve existing and develop new behavioral models of mental disorders and to search for new ways to study the mechanisms of formation of behavioral disorders.

We report here studies using an experimental model of autism created by prenatal administration of valproic acid to produce a comparative analysis of behavioral disorders in female and male rats, along with indicators of relative levels of expression of the Drd1 dopamine receptor gene in brain structures playing a significant role in disorders of social behavior and the development of anxiety – the prefrontal cortex, amygdala, cerebellum, and hippocampus. The state of anxiety in the valproate model of autism was found to develop only in males, while disorders of social behavior were typical of rats of both sexes, though the nature of these disorders differed in females and males: in the three-chamber social test, males preferred to spend more time in the compartment with a familiar animal, while females preferred to spend significantly less time with a novel, unfamiliar rat, as compared with control animals. Sex-related differences were found in the relative levels of expression of the Drd1 gene in the prefrontal cortex, amygdala, and cerebellum: the relative level of Drd1 expression was greater in the prefrontal cortex and amygdala in females, while males, conversely, showed significantly lower expression in the cerebellum in relation to both males of the control group and females. Analysis of the results obtained here indicates that there is a need to consider changes in the relative levels of Drd1 expression in all study areas simultaneously, evaluating the overall changes in the expression profiles of this gene, which may underlie sex-related differences in both communication disorders and other possible behavioral changes in the valproate model of autism in rats.

У крыс, перенесших острую перинатальную гипоксию, при достижении 2 мес были отмечены мнемотропные нарушения на модели условной реакции пассивного избегания, развитие депрессивноподобного состояния на модели «поведенческое отчаяние», повышение активности МАО Б в головном мозге. Введение препарата КАПАХ (2-хлорэтокси-пара-N-диметиламинофенилфосфорилацетогидразид) в дозе 10 мг/кг подкожно в раннем постнатальном периоде (с 8 по 12 дни жизни) в течение 2 недель предупреждало развитие этих нарушений, исследуемые показатели у них не отличались от таковых у интактных животных. Мнемотропное действие КАПАХ сходно с эффектом лиганда нейрокининовых NK1 рецепторов субстанции Р. Учитывая наличие аффинности у КАПАХ к нейрокининовым рецепторам, высказано предположение, что мнемотропный эффект КАПАХ, как и субстанции Р, реализуется через нейрокининовые NK1 рецепторы. В механизме предупреждения развития депрессивноподобного состояния препаратом КАПАХ играет роль способность угнетать активность фермента МАО Б.

С целью оптимизации скрининга новых психотропных соединений с использованием компьютерной программы PASS был осуществлен прогноз психотропной активности 47 новых соединений, относящихся к ряду арил(гидразинокарбонилметил)фосфиновых кислот, из которых были выделены 16 наиболее перспективных. Психотропная активность этих веществ была изучена на лабораторных животных с использованием поведенческих моделей. Для этих соединений была прогнозирована мнемотропная активность (Pa = 0,742 – 0,840), антидепрессивная активность (Pa = 0,543 – 0,663) и анксиолитическая активность (Pa = 0,330 – 0,642). Результаты экспериментального изучения психотропной активности производных арил(гидразинокарбонилметил)фосфиновых кислот показали, что соединения оказывают мнемотропное, антидепрессивное и анксиолитическое действие в дозах, составляющих 1/100 и 1/1000 от ДЛ50. Результаты экспериментального изучения мнемотропной, антидепрессивной и анксиолитической активности в целом совпадают с данными компьютерного прогноза по программе PASS.

Age-related development of behavioral disorders in transgenic mice with modeled Alzheimer’s disease carrying V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) genotype was assessed at the age of 7.5, 10 and 20 months in the following tests: open-field, plus maze, T-maze, conditioned passive avoidance response, rotarod, conflict situation with water deprivation, behavioral despair, and arecoline tremor. The main behavioral disorder in transgenic mice at all observation terms was memory impairment in conditioning with positive (but not negative) reinforcement. At the age of 7.5 and 10 months, transgenic mice also showed signs of nonspecific excitement and anxiety, depression-like state, and symptoms of cholinergic deficit. Our results suggest that appropriate age for behavioral tests in studies of effects of potential anti-Alzheimer drugs in transgenic V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) mice is 7.5-10 months.

A new compound, (2-chloroethoxy-4’-dimethylaminophenyl)phosphorylacetic acid N -acetohydrazide (II) has been synthesized. Compound II is proposed to be a metabolite of 2-(chloroethoxy-4’-dimethylaminophenyl)phosphoryl acetohydrazide (CAPAH, I) – a phosphorylacetic acid derivative possessing nootropic activity. Psychotropic and antiarrhythmic properties of II were studied in comparison to those of I. It is established that II does not possess nootropic and antidepressant activities, but its antiarrhythmic properties are more pronounced. It is suggested that C(O)CH 3 fragment, being a substitute of hydrazide in the structure of II, decreases penetration of this compound through blood-brain barrier, which can explain the absence of psychotropic activity.

The new compound (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid N-acetylhydrazide (II) was synthesized. Compound II was proposed as a metabolite of (2-chloroethoxy-4′-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH, I), a drug possessing nootropic activity. The psychotropic and antiarrhythmic properties of II were compared with those of I. It was established that II did not possess nootropic and antidepressant activities although its antiarrhythmic properties were more pronounced. It was suggested that the C(O)CH3 fragment, being a substituent on the hydrazide in II, decreased penetration of the compound through the blood―brain barrier, which could explain the absence of psychotropic activity.

Application of computer modeling to a series of phosphorylated carboxylic acid derivatives revealed new compounds possessing high psychotropic activity, i.e., hydrazinium salts of phosphorylacetohydrazides. It was proved experimentally that these compounds contributed to the improvement of memory and learning processes, possessed antihypoxic properties, and exhibited antidepressant activity. The pharmacologically relevant pharmacophores in this group were the methyl and fluorine atom in the phosphoryl aryl radical. The obtained results confirmed the expediency of using a complex analysis of computer modeling of the structure–activity relationship and an experimental search for pharmacophores for scientifically justified prognosis and design of new drugs.

Цель настоящей работы – провести анализ «химическая структура - нейротропная активность» среди производных фосфорилированных карбоновых кислот, экспериментально выявить фармакофоры и наиболее перспективные соединения. Проведен синтез, фармакологическое изучение и установление зависимости в ряду новых производных гидразидов фосфорилуксусной кислоты для определения направлений синтеза и изучения наиболее перспективных соединений. Анализ зависимости структура-нейротропная активность среди незамещенных фосфорилацетогидразидов выявил фармакофоры, синтезированы новые ряды соединений: соли арил,гидроксифосфорилацетогидразидов с общей формулой: 4-XPhP(O)(O-)CH2C(O)NHNH2•[Z+] с различной природой катионного и анионного фрагментов. На поведенческих моделях экспериментально изучена мнемотропная и антидепрессивная активность данных соединений, установлены функциональные группы, отвечающие за эти виды активностей. Среди изученных фосфорилацетогидразидов выявлены перспективные для дальнейшего изучения соединения – производные 4-хлорфенилфосфорилуксусной кислоты, даны рекомендации для направленного синтеза новых эффективных соединений.

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Nootropic non-anticholinesterase organophosphorus preparation CAPAH and substance P produced similar and dose-dependent effects on the amplitude and temporal parameters of miniature endplate potentials in mammalian neuromuscular synapse. Neurokinin receptor antagonist Win-51.708 abolished the effects of these agents. In behavioral experiments substance P moderated the mnemotropic and antidepressant effects of CAPAH. It was assumed that neurokinin receptors are the targets of CAPAH and substance P in CNS and neuromuscular synapse.

In vivo and in vitro experiments revealed the neuroprotective activity of CAPAH, a representative of the new nootropic class phosphorylated carboxylic acid hydrazides. The mechanisms of this action, which were due to the membranous stabilizing activity of the drug and its affinity for glycine strychnine-sensitive sites of MMDA receptors (Ki = 8.8.10(-5) M). Six analogues of CAPAH have been also found to have affinity for these types of receptors; based on the examination of structure-affinity relationship, putative pharmacophores (only radicals of the benzene ring of a molecule in the para position exerted effects on affinity changes) were revealed. The findings give a deep insight into the mechanism of nootropic activity and open vistas for synthesizing phosphorylated carboxylic acid hydrazides as potential neuroprotective agents interacting with glycine strychnine-sensitive sites of MMDA receptor.

The antidepressive effects of O-β-chloroethyl-para-N-dimethylphosphinylacetic acid (amphazide) are demonstrated on CBWA tetrahybrid male mice using the “behavioral despair” and “conditioned helplessness” models. The pharmacological effect of a course of amphazide appears more rapidly than that of the tricyclic antidepressant melipramine. The serotonin-positive activity of amphazide manifests itself, in particular, in a heightened reaction of stressed mice to injection of 5-hydroxytryptophan.