A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate gamma-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA(A) receptors. Many of these compounds enhanced GABA action with potencies (EC(50) = 0.19-19 muM) 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 [(3)H]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 beta2 subunit of the GABA(A) receptor into serine reduced the ability of derivative 1i to modulate the GABA function.