| Literature DB >> 16291941 |
Rebecca Dias1, Wayne F A Sheppard, Rosa L Fradley, Elizabeth M Garrett, Joanna L Stanley, Spencer J Tye, Simon Goodacre, Rachael J Lincoln, Susan M Cook, Rachel Conley, David Hallett, Alexander C Humphries, Sally A Thompson, Keith A Wafford, Leslie J Street, J Luis Castro, Paul J Whiting, Thomas W Rosahl, John R Atack, Ruth M McKernan, Gerard R Dawson, David S Reynolds.
Abstract
The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.Entities:
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Year: 2005 PMID： 16291941 PMCID： PMC6725841 DOI： 10.1523/JNEUROSCI.1166-05.2005
Source DB: PubMed Journal: J Neurosci ISSN： 0270-6474 Impact factor: 6.167