RESUMEN
This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.
Asunto(s)
Aminas/química , Ansiolíticos/síntesis química , Receptor del Glutamato Metabotropico 5/química , Administración Oral , Regulación Alostérica , Aminas/síntesis química , Aminas/farmacología , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Hipertermia Inducida , Ratones , Conformación Molecular , Receptor del Glutamato Metabotropico 5/metabolismo , Recto/efectos de los fármacos , Recto/fisiología , Estereoisomerismo , Relación Estructura-Actividad , TemperaturaRESUMEN
We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo.