RESUMEN
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Agonistas de Receptores de GABA-A , Nootrópicos/síntesis química , Ftalazinas/síntesis química , Triazoles/síntesis química , Animales , Unión Competitiva , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Convulsivantes/síntesis química , Convulsivantes/química , Convulsivantes/farmacología , Perros , Humanos , Macaca mulatta , Ratones , Nootrópicos/química , Nootrópicos/farmacología , Oocitos/metabolismo , Técnicas de Placa-Clamp , Ftalazinas/química , Ftalazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/fisiología , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Xenopus laevisRESUMEN
The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
Asunto(s)
Agonistas de Receptores de GABA-A , Isoxazoles/síntesis química , Ftalazinas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Línea Celular , Femenino , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Ftalazinas/química , Ftalazinas/farmacocinética , Ftalazinas/farmacología , Subunidades de Proteína/agonistas , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacología , Xenopus laevisRESUMEN
A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the alpha(3) over the alpha(1) containing subtype of the human GABA(A) receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam.