RESUMO
The synthesis of 5-[hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-1H-indole-7- carboxamide, 5, a pyrrolo analogue of labetalol, is described. Compound 5 was found to reduce blood pressure in spontaneously hypertensive rats with an ED50 of 5 mg/kg po, without causing any decrease in heart rate. Isolated tissue studies with 5 shows that it is a nonselective beta-adrenoceptor antagonist and that it is a weaker alpha-adrenoceptor antagonist with a relative selectivity for alpha 1-receptors. Additionally, the compound displayed significant beta-adrenoceptor intrinsic sympathomimetic activity. Evidence is presented that the beta-adrenoceptor antagonist and agonist properties of 5 are mediated via hydrogen-bond formation with the receptor.
Assuntos
Anti-Hipertensivos/farmacologia , Labetalol/análogos & derivados , Animais , Anti-Hipertensivos/síntese química , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Ligação de Hidrogênio , Técnicas In Vitro , Ratos , Ratos Endogâmicos SHR , Receptores Adrenérgicos beta/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of compounds was prepared in which the 1-methyl-3-phenylpropylamino moieties of the antihypertensive agents labetalol and medroxalol were replaced by 2-aminotetralins. Compounds containing a 6-methoxy and 6,7-methylenedioxy group in the aminotetralin were at least as active as labetalol in lowering the blood pressure of the spontaneously hypertensive rat (SHR). As determined by ligand binding, these compounds were comparable to labetalol as alpha 1-antagonists but were substantially weaker beta 1-antagonists.
