PT  - JOURNAL ARTICLE
AU  - Sullivan, Susan K.
AU  - Petroski, Robert E.
AU  - Verge, Gail
AU  - Gross, Raymond S.
AU  - Foster, Alan C.
AU  - Grigoriadis, Dimitri E.
TI  - Characterization of the Interaction of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic, with the GABA<sub>A</sub> Receptor
AID  - 10.1124/jpet.104.071282
DP  - 2004 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 537--546
VI  - 311
IP  - 2
4099  - http://jpet.aspetjournals.org/content/311/2/537.short
4100  - http://jpet.aspetjournals.org/content/311/2/537.full
SO  - J Pharmacol Exp Ther2004 Nov 01; 311
AB  - 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