RESUMEN
The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.
Asunto(s)
Anestésicos/farmacología , Etomidato/farmacología , Hipnóticos y Sedantes/farmacología , Receptores de GABA-A/metabolismo , Animales , Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Separación Celular , Estado de Conciencia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Marcación de Gen , Técnicas In Vitro , Masculino , Ratones , Ratones Mutantes , Actividad Motora/efectos de los fármacos , Técnicas de Placa-Clamp , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Células de Purkinje/citología , Células de Purkinje/efectos de los fármacos , Células de Purkinje/fisiología , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/genética , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/genética , Triazoles/farmacologíaRESUMEN
We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
Asunto(s)
Agonistas de Receptores de GABA-A , Ftalazinas/síntesis química , Triazoles/síntesis química , Animales , Sitios de Unión , Línea Celular , Femenino , Humanos , Modelos Moleculares , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Ftalazinas/química , Ftalazinas/farmacología , Subunidades de Proteína/agonistas , Subunidades de Proteína/fisiología , Ensayo de Unión Radioligante , Receptores de GABA-A/fisiología , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Xenopus laevisRESUMEN
A series of substituted 3,4-dihydronaphthalen-1(2H)-ones with high binding affinity for the benzodiazepine site of GABAA receptors containing the alpha5-subunit has been identified. These compounds have consistently higher binding affinity for the GABAA alpha5 receptor subtype over the other benzodiazepine-sensitive GABAA receptor subtypes (alpha1, alpha2 and alpha3). Compounds with a range of efficacies for the benzodiazepine site of alpha5-containing GABAA receptors were identified, including the alpha5 inverse agonist 3,3-dimethyl-8-methylthio-5-(pyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 22 and the alpha5 agonist 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one 19.