Abstract

Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high-affinity binding to native GABA_A receptors from rat brain and acts as a positive allosteric modulator of GABA_A receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABA_A receptor α subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABA_A receptors expressed in human embryonic kidney 293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABA_A receptors in a dose-dependent and reversible manner and was approximately 10-fold selective for α1 subunit-containing receptors over GABA_A receptors containing α2, α3, or α5 subunits. The EC₅₀ values were 2.6, 24, 60, and 77 nM for α1β2γ2, α2β2γ2, α3β3γ2, and α5β2γ2 receptors, respectively. Indiplon was approximately 10 times more potent than zolpidem and zopiclone and >100 times more potent than zaleplon. Moreover, indiplon, up to 1 μM, did not potentiate GABA_A receptors composed of α4β2γ2 and α6β2γ2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.