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NEUROPHARMACOLOGY

Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for 1 Subunit-Containing GABA_A Receptors

Departments of Neuroscience (R.E.P., J.E.P., R.D., H.B., A.P.C., A.C.F.) and Molecular Biology (W.Y.), Neurocrine Biosciences Inc., San Diego, California

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 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 1 subunit-containing receptors over GABA_A receptors containing 2, 3, or 5 subunits. The EC₅₀ values were 2.6, 24, 60, and 77 nM for 122, 222, 332, and 522 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 422 and 622 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.

Address correspondence to: Dr. Robert E. Petroski, Department of Neuroscience, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130. E-mail: rpetroski{at}neurocrine.com

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