RESUMO
Stereospecific requirements for the interaction of the thromboxane A(2) carbocyclic mimetic CTA(2) 1 with the human platelet PGH(2)/TXA(2) receptor have been explored. The two pairs of trans-1,2 and cis-3,4 side chain diastereoisomers were synthesised and evaluated for agonist and antagonist activity in human platelet rich plasma. Interestingly, the natural and unnatural trans diastereoisomers, both possessed potent aggregatory activity and equipotently inhibited platelet responses to subsequent addition of agonists, whereas, the respective unnatural cis isomers proved only weakly active or inert.
Assuntos
Plaquetas/efeitos dos fármacos , Tromboxano A2/farmacologia , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Estereoisomerismo , Tromboxano A2/químicaRESUMO
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 EndogâmicosAssuntos
Alprostadil/análogos & derivados , Prostaglandinas E Sintéticas/síntese química , Úlcera Gástrica/prevenção & controle , Animais , Indometacina/efeitos adversos , Espectroscopia de Ressonância Magnética , Prostaglandinas E Sintéticas/uso terapêutico , Ratos , Ratos Endogâmicos , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-AtividadeRESUMO
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-AtividadeAssuntos
Tromboxano A2/síntese química , Tromboxanos/síntese química , Animais , Artérias/efeitos dos fármacos , Bioensaio , Colágeno/farmacologia , Cobaias , Humanos , Pulmão/efeitos dos fármacos , Métodos , Contração Muscular/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Coelhos , Relação Estrutura-Atividade , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacologiaRESUMO
Primary trisomics were used to locate the structural loci coding for particular forms of the dimeric enzymes phosphoglucoisomerase and glutamate oxaloacetate transaminase in Lolium perenne. The polymorphy of these loci enabled triallelic trisomics to be produced. Each locus could thus be directly assigned to a particular chromosome without the need to examine segregant progeny. The loci for GOT/3 and PGI/2 were found to be located on chromosomes 2 and 6 respectively.
RESUMO
(+/-)-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.
Assuntos
Prostaglandinas E Sintéticas/síntese química , Prostaglandinas E Sintéticas/farmacologia , Alprostadil/análogos & derivados , Animais , Pressão Sanguínea/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Gatos , Fenômenos Químicos , Química , Relação Dose-Resposta a Droga , Feminino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Gravidez , Prostaglandinas E/farmacologia , Prostaglandinas E Sintéticas/administração & dosagem , Ratos , Contração Uterina/efeitos dos fármacosRESUMO
The synthesis and gastrointestinal pharmacology of some 11-deoxyprostaglandin E1 analogues are described with results analysed for selectivity from side effects. 11-Deoxygenation reduced potency relative to PGE2 but, as has been reported for natural PGs, 15- or 16-methyl analogues were more potent than the unsubstituted parent compound in the order 16-methyl greater than 15-methyl greater than 16,16-dimethyl. The results suggest that a complex interaction between C-15 and C-16 in methyl analogues affects their profile of activity, but that none of the modifications studied conferred a substantial potency or selectivity advantage over PGE2.
