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

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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 (<10%). This sedation liability of MRK-409 in man was attributed to its weak partial agonist efficacy at the α1 subtype since both TPA023 and TPA023B lacked any α1 efficacy and did not produce overt sedation even at relatively high levels of occupancy (≥50%). The anxiolytic efficacy of TPA023 was evaluated in Generalized Anxiety Disorder and although these clinical trials were terminated early due to preclinical toxicity issues, the combined data from these incomplete studies demonstrated an anxiolytic-like effect of TPA023. This compound also showed a trend to increase cognitive performance in a small group of schizophrenic subjects and is currently under further evaluation of its cognition-enhancing effects in schizophrenia as part of the TURNS initiative. In contrast, the fate of the back-up clinical candidate TPA023B has not been publicly disclosed. At the very least, these data indicate that the pharmacological profile of compounds that differentially modulate specific populations of GABAA receptors is distinct from classical benzodiazepines and should encourage further preclinical and clinical investigation of such compounds, with the caveat that, as exemplified by MRK-409, the preclinical profile might not necessarily translate into man. © Springer-Verlag Berlin Heidelberg 2009.




Atack, J. R. (2010). GABAA receptor α2/α3 subtype-selective modulators as potential nonsedating anxiolytics. Current Topics in Behavioral Neurosciences, 2, 331–360.

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