Anti-anxiety properties of new 5H-2,3-benzodiazepine and 5H-[1,2,5]triazepine derivatives

Abstract

Introduction: Previous studies have examined the anxiolytic properties of compounds containing mutually annulated systems of 5H-2,3-benzodiazepine and [1,2,4]triazole, namely 7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine derivatives. In the present work, another group of 5H-2,3-benzodiazepine and 5H-[1,2,5]triazepine derivatives was examined for psychotropic activity.

Materials and Methods: For in silico assay the PASS online test system and ADMET analysis were used. Compounds under study were also tested in vivo in Elevated Plus Maze, Open Field and Rotarod tests.

Results and Discussion: Of note is that the presence of a 3,4-dimethoxyphenyl substituent at position 4 of the diazepine ring (RD-1, RD-7) leads to a decrease in anxiolytic activity compared to 4-methoxyphenyl derivatives (RD-6, RD-9). Among the derivatives of condensed 5H-[1,2,5]triazepines, a more pronounced anti-anxiety effect was exerted by compound RD-8 with an annelated benzimidazole bicycle compared to its analog RD-15 with a pyrrole cycle. The high anxiolytic activity of the compounds is facilitated by the presence of slightly branched (RD-6, RD-9) or unbranched (RD-8) substituents in position 4 of the diazepine or triazepine cycle. In the Rotarod test, it was noted that 4-(3,4-dimethoxyphenyl)-1-hydrazino-5H-2,3-benzodiazepine (RD-1) and 4-hydrazino-7,8,9-trimethyl-1-phenyl-5H-pyrrolo[2,1-d][1,2,5]triazepine (RD-15) have a negative effect on muscle tone in mice due to the presence of a hydrazino group in their composition. According to ADMET analysis, compounds RD-6, RD-8 and RD-9 are low toxic; however, a specific toxicity study among these derivatives is recommended.

Conclusion: The most active and safe compound for further studies among the studied derivatives with a single administration is 1,4-diphenyl-5H-[1,2,5]triazepino[5,4-a]benzimidazole (RD-8) at a dose of 1.3 mg/kg.

Graphical Abstract