RESUMEN
There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.
Asunto(s)
Ansiolíticos/síntesis química , Agonistas de Receptores de GABA-A , Hipnóticos y Sedantes/síntesis química , Piridazinas/síntesis química , Triazoles/síntesis química , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Unión Competitiva , Línea Celular , Perros , Antagonistas de Receptores de GABA-A , Semivida , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Ratones , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Primates , Piridazinas/química , Piridazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/fisiología , Proteínas Recombinantes/agonistas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , XenopusRESUMEN
A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.