RESUMO
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-AtividadeAssuntos
Anafilaxia/prevenção & controle , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Liberação de Histamina/efeitos dos fármacos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Anafilaxia/metabolismo , Animais , Humanos , Pulmão/imunologia , Microssomos/efeitos dos fármacos , Microssomos/metabolismoRESUMO
A series of 1-(2-acyl-4-acylaminophenoxy)-3-isopropylaminopropan-2-ols has been synthesized and examined for beta-receptor blocking and antiarrhythmic activity. Several of these compounds are more than 20 times as active in blocking cardiac beta-receptors than vascular beta-receptors when given intravenously to anesthetized cats. The activities have been correlated quantitatively with partition and steric substitution constants. The observed relationships are consistent with a tentative proposal that the vascular receptor is situated in a more lipophilic environment than the cardiac receptor so that there is a differential transport effect between the two types of receptor.
Assuntos
Antagonistas Adrenérgicos beta/síntese química , Propanolaminas/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Anilidas/síntese química , Anilidas/farmacologia , Animais , Arritmias Cardíacas/induzido quimicamente , Gatos , Cães , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol/antagonistas & inibidores , Conformação Molecular , Especificidade de Órgãos , Ouabaína/antagonistas & inibidores , Propanolaminas/farmacologia , Receptores Adrenérgicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The synthesis and antiallergic activity in the rat passive cutaneous anaphylactic reaction of a series of 2-phenyl-8-azapurin-6-ones are described. Early in the investigation, a linear free-energy equation was established in which the activity was related to the size and hydrogen bonding capacity of the ortho substituent in the phenyl ring. This relationship was used to provide guidance and limits for subsequent work leading to 2-o-propoxyphenyl-8-azapurin-6-one which is 40 times more potent than disodium cromoglycate. It is suggested that good antiallergic activity in this series is associated with coplanarity of the phenyl group with the azapurin-6-one which would be favored by a high degree of hydrogen bonding.
