TY - JOUR T1 - Limiting Activity at β<sub>1</sub>-Subunit-Containing GABA<sub>A</sub> Receptor Subtypes Reduces Ataxia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1040 LP - 1053 DO - 10.1124/jpet.109.161885 VL - 332 IS - 3 AU - Kelvin W. Gee AU - Minhtam B. Tran AU - Derk J. Hogenkamp AU - Timothy B. Johnstone AU - Rudy E. Bagnera AU - Ryan F. Yoshimura AU - Jin-Cheng Huang AU - James D. Belluzzi AU - Edward R. Whittemore Y1 - 2010/03/01 UR - http://jpet.aspetjournals.org/content/332/3/1040.abstract N2 - GABAA receptor (R) positive allosteric modulators that selectively modulate GABAARs containing β2- and/or β3- over β1-subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,“β2/3-selective” GABAAR positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show α-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABAAR positive allosteric modulators that demonstrate differential β-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other β2/3-subunit selective, α-subunit isoform-selective, BZ and nonBZ GABAA positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at β1-subunit-containing GABAARs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABAAR with BZ-like anxiolytic efficacy by reducing or eliminating activity at β1-subunit-containing GABAARs.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -