Limiting activity at beta1-subunit-containing GABAA receptor subtypes reduces ataxia.
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.
Gee
Kelvin W
KW
Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA. kwgee@uci.edu
Tran
Minhtam B
MB
Hogenkamp
Derk J
DJ
Johnstone
Timothy B
TB
Bagnera
Rudy E
RE
Yoshimura
Ryan F
RF
Huang
Jin-Cheng
JC
Belluzzi
James D
JD
Whittemore
Edward R
ER
D000494:Allosteric Regulation; D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001259:Ataxia / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000577:Amides; D014151:Anti-Anxiety Agents; D018757:GABA Modulators; C546264:GABRB1 protein, human; C546266:Gabrb1 protein, mouse; D020033:Protein Isoforms; D011963:Receptors, GABA-A