RESUMO
Some (+)-11-deoxy-16-phenoxyprostaglandin E1 analogues have been evaluated as uterine stimulants in the anaesthetised pregnant rat. Gastrointestinal side effects, assessed by the antagonism of morphine-induced constipation in the mouse, were relatively low with some of these compounds, six of which had a much more favourable relative selectivity than 16,16-dimethyl-PGE2 methyl ester.
Assuntos
Alprostadil/análogos & derivados , Prostaglandinas E Sintéticas/farmacologia , Útero/efeitos dos fármacos , Animais , Sistema Digestório/efeitos dos fármacos , Feminino , Masculino , Camundongos , Morfina/farmacologia , Gravidez , Ratos , Ratos EndogâmicosRESUMO
Rat uterine stimulant activity has been determined in vivo for a series of (+)-11-deoxyprostaglandins. The most active members of the series. 11-deoxy-15 methyl-PGE1, 11-deoxy-16,16-dimethyl - PGE1 and its 1-alcohol were 2-3 times more potent than PGE1. Gastrointestinal side effects assessed by the antagonism of morphine-induced constipation in the mouse, were generally relatively low with these compounds and consequently several members of the series had a more favourable relative selectivity than 16,16-dimethyl-PGE2 methyl ester.
Assuntos
Prostaglandinas Sintéticas/farmacologia , Contração Uterina/efeitos dos fármacos , Animais , Constipação Intestinal/induzido quimicamente , Cricetinae , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Luteolíticos , Masculino , Camundongos , Morfina/antagonistas & inibidores , Prostaglandinas Sintéticas/síntese química , Ratos , Ratos EndogâmicosRESUMO
Some omega-chain phenyl- and 16-phenoxy- analogues of (+/-)-11-deoxyprostaglandin F1 alpha have been synthesized and evaluated for anti-fertility activity in the hamster. 11-Deoxy-16-phenoxy-17,18,19,20-tetranor-PGF1 alpha was the most active member of the series with an ED50 equal to that of PGF2 alpha. 11-Deoxy-17-phenyl-18,19,20-trinor-PGF1 alpha, which was one third as active as PGF2 alpha, was more potent than the corresponding 16- and 18-phenyl compounds. Aryl ring substitution was found to lower activity, except that with the 16-phenyl compound, p-bromo and m-trifluoromethyl substitution increased the potency. The antifertility activity of the phenoxy compounds, which were poor substrates for 15-hydroxyprostaglandin dehydrogenase, was shown to correlate well with the binding affinity for the bovine corpus luteum PGF2 alpha receptor. Some quantitative structure-activity data supporting this finding are presented.
Assuntos
Luteolíticos , Prostaglandinas F Sintéticas/farmacologia , Animais , Bovinos , Corpo Lúteo/metabolismo , Cricetinae , Feminino , Hidroxiprostaglandina Desidrogenases/metabolismo , Técnicas In Vitro , Pulmão/enzimologia , Masculino , Gravidez , Prostaglandinas F Sintéticas/síntese química , Prostaglandinas F Sintéticas/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
(+/-)-Deoxy-10-hydroxy-PGE1 methyl ester (Va) has been synthesised via conjugate addition of the cuprate (III) to the 5-tetrahydropyranyloxycyclopentenone (IId). Va was found to be 0.1 times as active as PGE1 as a uterine stimulant in the anaesthetized pregnant rat, 0.25 times as active as PGE1 in causing vasodepression in the anaesthetized cat, and approximately equiactive to PGE1 in inducing bronchoconstriction.
