Synthesis, Structure-Activity Relationships at the GABAA Receptor in Rat Brain, and Differential Electrophysiological Profile at the Recombinant Human GABAA Receptor of a Series of Substituted 1,2-Diphenylimidazoles

A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate γ-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABAA receptors. Many of these compounds enhanced GABA action with potencies (EC50 ) 0.19-19 μM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. Structure-activity relationship analysis revealed that the presence of an ester moiety in the imidazole ring was required for full agonist properties, while modifications made in the phenyl rings affected potency and efficacy, with ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H- 4-imidazolecarboxylate showing the highest potency. These compounds potentiated the [3H]- GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the 2 subunit of the GABAA receptor into serine reduced the ability of derivative 1i to modulate the GABA function.