Novel Derivatives of diphenyl-1,3,4-oxadiazol as Ligands of Benzodiazepine Receptors; Synthesize, Binding Assay and Pharmacological Evaluation

Benzodiazepines (BZD) are among the main classes of tranquilizing drugs, bearing much less toxicity compared to other drugs acting on the CNS. Considering the pharmacophore model of BZD binding to GABA-A receptor, novel diphenyl 1,3,4-oxadiazole compounds as BZD ligands were designed. The compounds were synthesized and structurally confirmed using LCMS, IR and NMR techniques. We investigated the affinity of the compounds to BZD receptors using radioligand [(3)H]-flumazenil by in-vitro studies. In addition, sedative-hypnotic, anxiety, anticonvulsant, muscle relaxant, memory impairment, and motor coordination activities of the synthesized compounds were evaluated using in-vivo studies. Based on in-vitro studies, compounds 7i and 7j were the most potent with IC(50) values of 1.54 and 1.66 nM respectively. In-vivo studies showed that compound 7i has the highest impact on increased sedation, muscle relaxation, and decreased anxiety and these observations were antagonized by flumazenil. Compounds 7e and 7i were the most potent anticonvulsant agents among synthesized compounds in both MES and PTZ induced seizure tests. All synthesized compounds significantly decreased latency to fall in the Rotarod test but none of them had a significant impact on the memory impairment test.