Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
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.
Asanuma,
GABAergic and pallidal terminals in the thalamic reticular nucleus of squirrel monkeys.
1994, Pubmed
Asanuma,
GABAergic and pallidal terminals in the thalamic reticular nucleus of squirrel monkeys.
1994,
Pubmed Bare,
Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents.
1989,
Pubmed Basile,
Anxioselective anxiolytics: can less be more?
2004,
Pubmed Bourin,
Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.
1992,
Pubmed Crabbe,
Genetic determinants of sensitivity to diazepam in inbred mice.
1998,
Pubmed Cryer,
Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs.
1998,
Pubmed Daly,
Non-xanthine heterocycles: activity as antagonists of A1- and A2-adenosine receptors.
1988,
Pubmed de Haas,
The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers.
2009,
Pubmed de Haas,
Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA(A) alpha2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers.
2008,
Pubmed Fisher,
Clobazam, oxcarbazepine, tiagabine, topiramate, and other new antiepileptic drugs.
1995,
Pubmed Groves,
The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole.
2006,
Pubmed Halliwell,
Subunit-selective modulation of GABAA receptors by the non-steroidal anti-inflammatory agent, mefenamic acid.
1999,
Pubmed
,
Xenbase Hamon,
The modulatory effects of the anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit.
2003,
Pubmed
,
Xenbase Harrison,
Mechanisms of sleep induction by GABA(A) receptor agonists.
2007,
Pubmed Hartings,
High responsiveness and direction sensitivity of neurons in the rat thalamic reticular nucleus to vibrissa deflections.
2000,
Pubmed Hazrati,
Projection from the external pallidum to the reticular thalamic nucleus in the squirrel monkey.
1991,
Pubmed Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase Hogenkamp,
Enaminone amides as novel orally active GABAA receptor modulators.
2007,
Pubmed Huntsman,
Fast IPSCs in rat thalamic reticular nucleus require the GABAA receptor beta1 subunit.
2006,
Pubmed Lippa,
Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator.
2005,
Pubmed
,
Xenbase LITCHFIELD,
A simplified method of evaluating dose-effect experiments.
1949,
Pubmed McCormick,
Sleep and arousal: thalamocortical mechanisms.
1997,
Pubmed McKernan,
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
2000,
Pubmed Ng,
Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.
2007,
Pubmed
,
Xenbase Nguyen,
Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice.
2006,
Pubmed Paré,
Substantia nigra pars reticulata projects to the reticular thalamic nucleus of the cat: a morphological and electrophysiological study.
1990,
Pubmed Pirker,
GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.
2000,
Pubmed Popik,
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 alpha1 subunit-containing GABAA receptors.
2006,
Pubmed
,
Xenbase Rudolph,
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
1999,
Pubmed Smith,
Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors.
2004,
Pubmed Sun,
Distribution of alpha1, alpha4, gamma2, and delta subunits of GABAA receptors in hippocampal granule cells.
2004,
Pubmed Thompson,
Tracazolate reveals a novel type of allosteric interaction with recombinant gamma-aminobutyric acid(A) receptors.
2002,
Pubmed
,
Xenbase Van der Werf,
The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness.
2002,
Pubmed Van Dort,
Adenosine A(1) and A(2A) receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal.
2009,
Pubmed Whiting,
GABA-A receptors: a viable target for novel anxiolytics?
2006,
Pubmed
