TY - JOUR T1 - Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABA<sub>A</sub> Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 369 LP - 377 DO - 10.1124/jpet.105.096701 VL - 317 IS - 1 AU - Robert E. Petroski AU - Jordan E. Pomeroy AU - Ronnie Das AU - Heath Bowman AU - Weidong Yang AU - Adele P. Chen AU - Alan C. Foster Y1 - 2006/04/01 UR - http://jpet.aspetjournals.org/content/317/1/369.abstract N2 - 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 GABAA receptors from rat brain and acts as a positive allosteric modulator of GABAA receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABAA receptor α subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABAA receptors expressed in human embryonic kidney 293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABAA receptors in a dose-dependent and reversible manner and was approximately 10-fold selective for α1 subunit-containing receptors over GABAA 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 &gt;100 times more potent than zaleplon. Moreover, indiplon, up to 1 μM, did not potentiate GABAA 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. The American Society for Pharmacology and Experimental Therapeutics ER -