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A number of novel 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole derivatives 2 were obtained by alkylation mainly in the 1H-tautomeric form of 2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole or its 8,9-dimethyl-substituted analog 4-chlorobenzyl bromide, 4-chloroacetic acid fluoroanilide, and 4-tert-butylphenacyl bromide in neutral medium. Compounds 3 were cyclized and synthesized earlier with 11-phenacyl-substituted diazepino[1,2-a]benzimidazoles upon heating in conc. HBr. The chemical structures of the compounds were clarified by using the 1H Nuclear Magnetic Resonance Spectroscopy (1H-NMR) technique. Anxiolytic properties were evaluated using the elevated plus maze (EPM) and open field (OF) tests. The analgesic effect of compounds was estimated with the tail flick (TF) and hot plate (HP) methods. Besides, possible the influence of the test compounds on motor activities of the animals was examined by the Grid, Wire, and Rotarod tests. Compounds 2d and 3b were the most active due to their prominent analgesic and anxiolytic potentials, respectively. The results of the performed in silico analysis showed that the high anxiolytic activity of compound 3b is explained by the combination of a pronounced interaction mainly with the benzodiazepine site of the GABAA receptor with a prominent interaction with both the specific and allosteric sites of the 5-HT2A receptor.

Изучена антидепрессивная активность 11-[4-трет-бутилбензил]-2,3,4,5-тетрагидро[1,3]диазепино[1,2-a]-бензимидазола гидробромида (ДАБ-19), и его возможных взаимодействий с ГАМК-рецепторами и основными катехоламинами ЦНС, а также моноаминоксидазной активности. По результатам проведенного исследования показано, что ДАБ-19 в дозе 2,34 мг/кг обладает умеренной антидепрессивной активностью на модели «Принудительное плавание по Porsolt», (78,0 ± 7,30) с для ДАБ-19 и (98,32 ± 11,54) с для группы контроля, и «Подвешивание за хвост», (110,1 ± 12,67) с для ДАБ-19 и (168,6 ± 10,2) с для контроля, на мышах (p ≤ 0,05). По результатам тестов «Апоморфиновая стереотипия» и «Стереотипия, обусловленная введением L-ДОФА» не было выявлено дофаминергической и моноаминоксидазной активности ДАБ-19 (p ≤ 0,05). Предположено наличие α2-адреноблокирующего и серотонинактивирующего действия изучаемой субстанции в тестах «5-Гидрокситриптофановый гиперкинез» и «Клофелиновая гипотермия». Антагонизм ДАБ-19 в дозе 2,34 мг/кг с флумазенилом (1 мг/кг) свидетельствует о связи психотропной активности ДАБ-19 с ГАМК-бензодиазепиновым рецепторным комплексом: время, проведенное животными в светлом рукаве для ДАБ-19 составило (78,6 ± 12,13) с, для ДАБ-19 + флумазенил — (6,7 ± 4,59) с (p ≤ 0,05).

Introduction: Diazepino[1,2-a]benzimidazole derivatives showed anxiolytic (EPM, L/D box, Vogel test), antidepressant (Tail Suspension test, Porsolt test), anticonvulsant (Pentylenetetrazole-Induced seizures) and analgesic (Tail-Flick, Hot Plate) actions, which were described earlier (Spasov et al. 2020). 11-(4-tert-butylbenzyl)-2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole hydrobromide (compound DAB-19) has evident anxiolytic, antidepressant and anticonvulsant effects. In the present study, compound DAB-19 was screened for its influence on animals` behavior patterns, such as aggression, obsessive-compulsive behavior, emotional lability, and unsociability. Materials and methods: 112 outbred white animals (rats and mice) were used. Compound DAB-19 (2.34 mg/kg, p.o.) and diazepam (2 mg/kg, p.o.) were injected to the treatment groups. Using an Open Field (OF) test, we evaluated a spontaneous motor activity, a search activity of mice and a degree of their emotionality. During a Marble Burying (MB) test, we monitored anxiolytic and anticompulsive effects of DAB-19. Using a Resident-intruder (RI) test, we evaluated a degree of aggression in the experimental animals, properties of their social interaction, as well as defensive and individual behavior. Results and discussion: Compound DAB-19 has positive influence on the search activity, mood stabilizing activity and antiaggressive actions. Administration of both DAB-19 (2.34 mg/kg, p.o.) and diazepam (2 mg/kg, p.o.) reduced anxiety-like behavior in OP, RI and MB tests, as indicated by a significantly increased number of entries to the center of OP; a decreased number of marbles buried in MB and reduced aggressive behavior in RI. It was stated that using DAB-19 leads to a decrease in affective reactions of the animals – aggression, obsessive-compulsive behavior, neurotic condition and emotional instability. Conclusions: The compound (DAB-19) produces anxiolytic-like effects, compared with those of diazepam, in various anxiety paradigms.

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