The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α1 Subunit-Containing GABAA Receptors

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Abstract
Studies using mice with point mutations of GABAA receptor α subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABAA receptors bearing the α1 and α2 subunits. This hypothesis predicts that a compound with high efficacy at GABAA receptors containing the α1 subunit would produce sedation, whereas an agonist acting at α2 subunit-containing receptors (with low or null efficacy at α1-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABAA receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at α1β2γ2S constructs of the GABAA receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing α2, α3, or α5 subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABAA1a receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by α1 subunit-containing GABAA receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.