title: Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors.
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 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 alpha1 subunit-containing receptors over GABA(A) receptors containing alpha2, alpha3, or alpha5 subunits. The EC(50) values were 2.6, 24, 60, and 77 nM for alpha1beta2gamma2, alpha2beta2gamma2, alpha3beta3gamma2, and alpha5beta2gamma2 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 microM, did not potentiate GABA(A) receptors composed of alpha4beta2gamma2 and alpha6beta2gamma2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.
authors.affiliation: Department of Neuroscience, Neurocrine Biosciences Inc., San Diego, CA 92130, USA. rpetroski@neurocrine.com
authors.forename: Robert E
authors.initials: RE
authors.lastname: Petroski
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Pomeroy
authors.forename: Ronnie
authors.initials: R
authors.lastname: Das
authors.forename: Heath
authors.initials: H
authors.lastname: Bowman
authors.forename: Weidong
authors.initials: W
authors.lastname: Yang
authors.forename: Adele P
authors.initials: AP
authors.lastname: Chen
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C546240:GABRA1 protein, human; C546242:Gabra1 protein, rat; D006993:Hypnotics and Sedatives; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D013876:Thiophenes; D001569:Benzodiazepines; C469870:indiplon