Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Mental Health [Grant MH082241]; and the University of California Discovery [Grant bio06-10577] (to K.W.G.). Parts of this work were previously presented by Bagnera RE, Johnstone TBC, Tran MB, Whittemore ER, Hogenkamp DJ, and Gee KW (2007) Characterization of a series of novel allosteric modulators of GABAA receptors with differential beta subunit selectivity. The Society for Neuroscience Conference; 2007 Oct 3–Nov 7; San Diego, CA. Society for Neuroscience, Washington, DC.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.161885.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- R
- receptor
- BZ
- benzodiazepine
- nonBZ
- nonbenzodiazepine
- DMSO
- dimethyl sulfoxide
- 5-HT
- 5-hydroxytryptamine
- nAChR
- nicotinic acetylcholine receptor
- HPLC
- high-performance liquid chromatography
- LD
- light-dark transition
- ANOVA
- analysis of variance
- RR
- Rotarod
- AD50
- ataxogenic half-maximal dose where half of the mice fail the RR assay
- EtOH
- ethanol
- MED
- minimal effective dose
- EPM
- elevated plus maze
- PK
- pharmacokinetic
- PD
- pharmacodynamic
- AI
- anxioselective index
- SAR
- structure-activity relationship
- LGIC
- ligand-gated ion channel.
- Received September 21, 2009.
- Accepted November 18, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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