GABAA receptor α2/α3 subtype-selective modulators as potential nonsedating anxiolytics

Nonselective benzodiazepines exert their pharmacological effects via GABAA receptors containing either an α1, α2, α3, or α5 subunit. The use of subtype-selective tool compounds along with transgenic mice has formed the conceptual framework for defining the requirements of subtype-selective compounds with potentially novel pharmacological profiles. More specifically, compounds which allosterically modulate the α2 and/or α3 subtypes but are devoid of, or have much reduced, effects at the α1 subtype are hypothesized to be anxioselective (i.e., anxiolytic but devoid of sedation). Accordingly, three compounds, MRK-409, TPA023 and TPA023B, which selectively potentiated the effects of GABA at the α2 and α3 compared to α1 subtypes were progressed into man. All three compounds behaved as nonsedating anxiolytics in preclinical (rodent and primate) species but, surprisingly, MRK-409 produced sedation in man at relatively low levels of occupancy (