TY - JOUR T1 - Characterization of the Interaction of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic, with the GABA<sub>A</sub> Receptor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 537 LP - 546 DO - 10.1124/jpet.104.071282 VL - 311 IS - 2 AU - Susan K. Sullivan AU - Robert E. Petroski AU - Gail Verge AU - Raymond S. Gross AU - Alan C. Foster AU - Dimitri E. Grigoriadis Y1 - 2004/11/01 UR - http://jpet.aspetjournals.org/content/311/2/537.abstract N2 - 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 GABAA receptor. Indiplon is a novel pyrazolopyrimidine sedative-hypnotic agent, currently in development for insomnia. Using radioligand binding studies, indiplon inhibited the binding of [3H]Ro 15-1788 (flumazenil) to rat cerebellar and cerebral cortex membranes with high affinity (Ki values of 0.55 and 0.45 nM, respectively). [3H]Indiplon binding to rat cerebellar and cerebral cortex membranes was reversible and of high affinity, with KD values of 1.01 and 0.45 nM, respectively, with a pharmacological specificity consistent with preferential labeling of GABAA receptors containing α1 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 GABAA 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 GABAA receptor. The American Society for Pharmacology and Experimental Therapeutics ER -