Novel agonists of benzodiazepine receptors: Design, synthesis, binding assay and pharmacological evaluation of diphenyl-1,2,4-triazole derivatives

Abstract

Benzodiazepines (BZD) are widely used in neurological disorders. The use of classical benzodiazepines is limited due to side effects. In this study, based on the structure–activity relationship (SAR) of Benzodiazepine receptors, new derivatives of 4-amino-3,5-diphenyl-1,2,4-triazole as benzodiazepine agonists with selective effects were designed and synthesized. Docking studies showed that pharmacophore groups of the designed structures and zolpidem, a benzodiazepine receptor agonist, are properly matched and are located well in the GABA receptor. The triazole group of the compound 4j, N N-(3,5-diphenyl-4H-1,2,4-triazol-4-yl)-2-((4-fluorobenzyl)amino)acetamide, was near the nitrogen moiety of the imidazole ring of zolpidem providing the hydrogen bond acceptor in the suitable direction in the BDZ-binding site of GABAA receptor model (α1β2ϒ2). The compounds were synthesized with acceptable yield and in-vitro affinity for the BZD receptor was determined. Compound 4j had the best affinity for the BZD site of action on GABAA receptor complex (Ki = 2.56 nM and IC50 = 6.10 nM). In addition, the sedative-hypnotic effect, the locomotor activity, and evaluated memory of the novel compounds were assessed by pentobarbital-induced sleeping, open field, and passive avoidance tests respectively. Most of the novel compounds showed significant hypnotic activity with no impairment on learning and memory performance in the mouse. The pharmacological effects of the compounds were antagonized by flumazenil, a BZD antagonist, which confirms the involvement of BZD receptors in the biological effects.

Keywords

• Benzodiazepine
• Binding assay
• 1,2,4-triazole
• Docking
• Hypnotic