Indiplon is a high-affinity positive allosteric modulator with selectivity for α1 subunit-containing GABAA receptors

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 alpha 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 alpha 1 subunit-containing receptors over GABA(A) receptors containing alpha 2, alpha 3, or alpha 5 subunits. The EC50 values were 2.6, 24, 60, and 77 nM for alpha 1 beta 2 gamma 2, alpha 2 beta 2 gamma 2, alpha 3 beta 3 gamma 2, and alpha 5 beta 2 gamma 2 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 mu M, did not potentiate GABA(A) receptors composed of alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.