New insight into the central benzodiazepine receptor-ligand interactions: Design, synthesis, biological evaluation, and molecular modeling of 3-substituted 6-phenyl-4 H -imidazo[1,5- a][1,4]benzodiazepines and related compounds

摘要

3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K_i values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of ~(36)Cl~- in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α_1β _2γ_2L, α_2β_1γ _2L, and α_5β_2γ_2L human GABA_A receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer's GABA_A homology model.