RESUMEN
The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Asunto(s)
Ansiolíticos/síntesis química , Agonistas de Receptores de GABA-A , Imidazoles/síntesis química , Triazinas/síntesis química , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Disponibilidad Biológica , Semivida , Humanos , Imidazoles/química , Imidazoles/farmacología , Técnicas de Placa-Clamp , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/fisiología , Saimiri , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacologíaRESUMEN
(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (13) has been identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors. 13 is orally bioavailable, readily penetrates the CNS, and enhances performance in animal models of cognition. It does not exhibit the convulsant, proconvulsant, or anxiogenic activity associated with nonselective GABA(A) inverse agonists.
Asunto(s)
Cognición/efectos de los fármacos , Agonistas de Receptores de GABA-A , Isoxazoles/síntesis química , Nootrópicos/síntesis química , Triazinas/síntesis química , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Perros , Isoxazoles/efectos adversos , Isoxazoles/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Nootrópicos/efectos adversos , Nootrópicos/farmacología , Técnicas de Placa-Clamp , Subunidades de Proteína , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/metabolismo , Triazinas/efectos adversos , Triazinas/farmacologíaRESUMEN
Inbred strains of mice are known to differ in their performance in the Morris water maze task, a test of spatial discrimination and place navigation in rodents, but the genetic basis of individual variation in spatial learning is unknown. We have mapped genetic effects that contribute to the difference between two strains, DBA/2 and C57BL6/J, using an F2 intercross and methods to detect quantitative trait loci (QTL). We found two QTL, one on chromosome 4 and one on chromosome 12, that influence behavior in the probe trial of the water maze (genome-wide significance p = 0.017 and 0.015, respectively). By including tests of avoidance conditioning and behavior in a novel environment, we show that the QTL on chromosomes 4 and 12 specifically influence variation in spatial learning. QTL that influence differences in fearful behavior (on chromosomes 1, 3, 7, 15, and 19) operate while mice are trained in the water maze apparatus.
