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

3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related com- pounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their Ki values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of 36Cl 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 R1β2γ2L, R2β1γ2L, and R5β2γ2L human GABAA receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromer’s GABAA homology model.