RESUMEN
In pursuit of a GABA(A) alpha5-subtype-selective inverse agonist to enhance cognition, a series of 6,7-dihydro-2-benzothiophen-4(5H)-ones has been identified as a novel class of GABA(A) receptor ligands. These thiophenes have higher binding affinity for the GABA(A) alpha5 receptor subtype compared to the GABA(A) alpha1, alpha2, and alpha3 subtypes, and several analogues exhibit high GABA(A) alpha5 receptor inverse agonism. 6,6-Dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (43) has been identified as a full inverse agonist at the GABA(A) alpha5 receptor and is functionally selective over the other major GABA(A) receptor subtypes. 43 readily penetrates into the CNS to give selective occupancy of GABA(A) alpha5 receptors. In addition, 43 enhances cognitive performance in rats in the delayed 'matching-to-place' Morris water maze test-a hippocampal-dependent memory task-without the convulsant or proconvulsant activity associated with nonselective, GABA(A) receptor inverse agonists.
Asunto(s)
Cognición/efectos de los fármacos , Agonistas del GABA/síntesis química , Nootrópicos/síntesis química , Receptores de GABA-A/efectos de los fármacos , Tiazoles/síntesis química , Tiofenos/síntesis química , Animales , Encéfalo/metabolismo , Línea Celular , Femenino , Agonistas del GABA/efectos adversos , Agonistas del GABA/farmacología , Hipocampo/fisiología , Humanos , Técnicas In Vitro , Ligandos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Nootrópicos/efectos adversos , Nootrópicos/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Subunidades de Proteína , Ensayo de Unión Radioligante , Ratas , Convulsiones/inducido químicamente , Relación Estructura-Actividad , Tiazoles/efectos adversos , Tiazoles/farmacología , Tiofenos/efectos adversos , Tiofenos/farmacología , Xenopus laevisRESUMEN
Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.
Asunto(s)
Agonistas de Receptores de GABA-A , Cetonas/síntesis química , Tiofenos/síntesis química , Animales , Células Cultivadas , Cognición , Humanos , Cetonas/farmacología , Ratones , Tiazoles/síntesis química , Tiazoles/farmacología , Tiofenos/farmacología , Xenopus laevisRESUMEN
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 new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the rates of racemization to be measured and hence the free energy barrier for flipping the seven-membered ring to be deduced. Introduction of a further element of planar chirality leads to diastereomeric atropisomerism. The rate of interconversion of the diastereomers has been quantified by 2D EXSY NMR spectroscopy allowing a full description of the conformational dynamics of the system.