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NEUROPHARMACOLOGY

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 ₁ Subunit-Containing GABA_A Receptors

Behavioral Neuroscience (P.P., M.K.) and Department of Neurobiology (G.N., B.S.), Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland; Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts (E.K., S.J.R., T.T.G., D.H.F.); Department of Cytobiology and Histochemistry, Collegium Medicum, Jagiellonian University, Krakow, Poland (G.N.); and DOV Pharmaceutical, Inc., Somerset, New Jersey (P.K., Z.C., P.S., A.S.L., A.S.B.)

Studies using mice with point mutations of GABA_A receptor subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA_A receptors bearing the ₁ and ₂ subunits. This hypothesis predicts that a compound with high efficacy at GABA_A receptors containing the ₁ subunit would produce sedation, whereas an agonist acting at ₂ subunit-containing receptors (with low or null efficacy at ₁-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA_A receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at _122S constructs of the GABA_A 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 ₂, ₃, or ₅ 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 GABA_A1a receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by ₁ subunit-containing GABA_A receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.

Address correspondence to: Dr. Anthony S. Basile, DOV Pharmaceutical, Inc., 150 Pierce St., Somerset, NJ 08873-4185. E-mail: asbasile{at}dovpharm.com

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				A. S. Basile, A. Janowsky, K. Golembiowska, M. Kowalska, E. Tam, M. Benveniste, P. Popik, A. Nikiforuk, M. Krawczyk, G. Nowak, et al. Characterization of the Antinociceptive Actions of Bicifadine in Models of Acute, Persistent, and Chronic Pain J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1208 - 1225. [Abstract] [Full Text] [PDF]