title: Characterization of the interaction of indiplon, a novel pyrazolopyrimidine sedative-hypnotic, with the GABAA receptor.
abstract: Clinically used benzodiazepine and nonbenzodiazepine sedative-hypnotic agents for the treatment of insomnia produce their therapeutic effects through allosteric enhancement of the effects of the inhibitory neurotransmitter GABA at the GABA(A) receptor. Indiplon is a novel pyrazolopyrimidine sedative-hypnotic agent, currently in development for insomnia. Using radioligand binding studies, indiplon inhibited the binding of [(3)H]Ro 15-1788 (flumazenil) to rat cerebellar and cerebral cortex membranes with high affinity (K(i) values of 0.55 and 0.45 nM, respectively). [(3)H]Indiplon binding to rat cerebellar and cerebral cortex membranes was reversible and of high affinity, with K(D) values of 1.01 and 0.45 nM, respectively, with a pharmacological specificity consistent with preferential labeling of GABA(A) receptors containing alpha1 subunits. In "GABA shift" experiments and in measurements of GABA-induced chloride conductance in rat cortical neurons in culture, indiplon behaved as an efficacious potentiator of GABA(A) receptor function. In both the radioligand binding and electrophysiological experiments, indiplon had a higher affinity than zolpidem or zaleplon. These in vitro properties are consistent with the in vivo properties of indiplon as an effective sedative-hypnotic acting through allosteric potentiation of the GABA(A) receptor.
authors.affiliation: Department of Pharmacology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Sullivan
authors.forename: Robert E
authors.initials: RE
authors.lastname: Petroski
authors.forename: Gail
authors.initials: G
authors.lastname: Verge
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Gross
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D018118:Chloride Channels / Q000502:physiology; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*; D014229:Triazolam / Q000494:pharmacology; D014316:Tritium; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000081:Acetamides; D001386:Azides; D018118:Chloride Channels; D018757:GABA Modulators; D011725:Pyridines; D011743:Pyrimidines; D011963:Receptors, GABA-A; D013876:Thiophenes; D014316:Tritium; D001569:Benzodiazepines; D014229:Triazolam; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; C469870:indiplon; C042957:Ro 15-4513; C085665:zaleplon