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 [³H]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). [³H]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 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 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.