Characterization of the Interaction of Indiplon, a Novel Pyrazolopyrimidine Sedative/Hypnotic, with the GABAA Receptor
Sullivan SK, Petroski RE, Verge G, Gross RS,
Foster AC, Grigoriadis DE.
Neurocrine Biosciences Inc.
J Pharmacol Exp Ther. 2004 Jul 15


Clinically used benzodiazepine and non-benzodiazepine sedative-hypnotic agents for the treatment of insomnia produce their therapeutic effects through allosteric enhancement of the effects of the inhibitory neurotransmitter, gamma-aminobutyric acid (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 [(3)H] Ro 15-1788 to rat cerebellar and cerebral cortex membranes with high affinity (Ki 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 KD values of 1.01 and 0.45 nM, respectively, with a pharmacological specificity consistent with preferential labeling of GABAA receptors containing a1 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 (Foster et al., 2004) as an effective sedative- hypnotic acting through allosteric potentiation of the GABAA receptor.
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