RESUMEN
Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.
Asunto(s)
Androstanoles/síntesis química , Anestésicos/síntesis química , Moduladores del GABA/síntesis química , Receptores de GABA-A/efectos de los fármacos , Androstanoles/química , Androstanoles/farmacología , Anestésicos/química , Anestésicos/farmacología , Animales , Encéfalo/metabolismo , Moduladores del GABA/química , Moduladores del GABA/farmacología , Enlace de Hidrógeno , Técnicas In Vitro , Inyecciones Intravenosas , Ratones , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/metabolismo , Relación Estructura-ActividadRESUMEN
(3 alpha,5 alpha)-3-Hydroxypregnan-20-ones and (3 alpha,5 alpha)-3-hydroxypregnane-11,20-diones bearing a 2 beta-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2 beta,3 alpha,5 alpha)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2 beta,3 alpha,5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABAA receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABAA receptors.
Asunto(s)
Anestesia , Anestésicos/síntesis química , Morfolinas/síntesis química , Pregnanodionas/síntesis química , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/fisiología , Animales , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Bovinos , Membrana Celular/metabolismo , Sistema Cromafín/fisiología , Conductividad Eléctrica , Electrofisiología , Masculino , Ratones , Estructura Molecular , Morfolinas/metabolismo , Morfolinas/farmacología , Pregnanodionas/metabolismo , Pregnanodionas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , AguaRESUMEN
In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg.