Asunto(s)
Factor Natriurético Atrial/síntesis química , Secuencia de Aminoácidos , Animales , Factor Natriurético Atrial/química , Factor Natriurético Atrial/farmacología , Técnicas In Vitro , Masculino , Datos de Secuencia Molecular , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , Conejos , Ratas , Relación Estructura-ActividadRESUMEN
3 beta-Amino compounds with 17 beta-(3-furyl) and (4-pyridazinyl) ring systems were prepared from digitoxigenin 1b and found to have similar cardiotonic properties to the analogous 3 beta-hydroxy compounds when tested in the isolated guinea-pig atrial preparation. Derivatives with 3 alpha-acetoxy functions were found to have higher than expected activities. Particularly potent was the pyridazine N1-oxide 19. All isocardenolides and the unsaturated anhydride 18 were devoid of activity.
Asunto(s)
Cardiotónicos/síntesis química , Digitoxigenina/análogos & derivados , Animales , Digitoxigenina/síntesis química , Digitoxigenina/farmacología , Cobayas , Técnicas In Vitro , Contracción Miocárdica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
3 alpha-Amino 1a and 3 beta-amino 1b analogues of digoxigenin 14 and their 12 beta-acetate derivatives 2a and 2b were prepared and tested for inotropic activity in the isolated guinea-pig atrial preparation. The 3 alpha-amino compounds were inactive whereas the 3 beta-amino compounds showed comparable activity to their 3 beta-hydroxy counterparts. The replacement of the 17 beta-butenolide ring by other ring systems was investigated. Compounds with a 3'-furyl ring, 9b and 16 were found to possess appreciable activity. A compound with a 4'-pyridazinyl ring 13b exhibited weak activity, whereas the isomeric butenolide compound 11b proved inactive. N-monomethylation of the amine 2b reduced activity and N-dimethylation abolished activity. Acetylation of the 12 beta-hydroxyl function gave less active compounds.
Asunto(s)
Digoxigenina/análogos & derivados , Digoxina/análogos & derivados , Animales , Cardiotónicos/síntesis química , Digoxigenina/síntesis química , Digoxigenina/farmacología , Cobayas , Técnicas In Vitro , Contracción Miocárdica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.
