Limiting Activity at beta(1)-Subunit-Containing GABA(A) Receptor Subtypes Reduces Ataxia

作者：Gee Kelvin W^*; Tran Minhtam B; Hogenkamp Derk J; Johnstone Timothy B; Bagnera Rudy E; Yoshimura Ryan F; Huang Jin Cheng; Belluzzi James D; Whittemore Edward R

来源：Journal of Pharmacology and Experimental Therapeutics, 2010, 332(3): 1040-1053.

DOI：10.1124/jpet.109.161885

GABA(A) receptor (R) positive allosteric modulators that selectively modulate GABA(A)Rs containing beta(2)- and/or beta(3)- over beta(1)- subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"beta(2/3)-selective" GABA(A)R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show alpha-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 GABA(A)R positive allosteric modulators that demonstrate differential beta-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other beta(2/3)-subunit selective, alpha-subunit isoform-selective, BZ and nonBZ GABA(A) positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at beta(1)-subunit-containing GABA(A)Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA(A)R with BZ-like anxiolytic efficacy by reducing or eliminating activity at beta(1)-subunit-containing GABA(A)Rs.

• 出版日期2010-3