RESUMEN
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.
Asunto(s)
Ansiolíticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Subunidades de Proteína/fisiología , Receptores de GABA-A/fisiología , Animales , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Benzodiazepinas/farmacología , Relación Dosis-Respuesta a Droga , Agonistas de Receptores de GABA-A , Humanos , Masculino , Ratones , Ratones Transgénicos , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , SaimiriRESUMEN
A new series of gamma-secretase inhibitors was developed from an in-house screening hit based on a benzobicyclo[4.2.1]nonane core. Lead optimisation studies led to the development of a series of potent inhibitors and in vivo efficacy was demonstrated.