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 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.
Footnotes
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doi:10.1124/jpet.104.071282.
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ABBREVIATIONS: Indiplon, NBI 34060, N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-α]pyrimidin-7-yl]phenyl]acetamide; Ro 15-1788, flumazenil; Ro 15-4513, ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylate; DMSO, dimethyl sulfoxide.
- Received May 11, 2004.
- Accepted July 9, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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