RESUMEN
High affinity binding sites for [3H]leukotriene C4 ([3H]LTC4) have been identified and characterised in guinea-pig lung membranes. [3H]LTC4 bound to these membranes with a pharmacological specificity totally distinct to that previously observed for [3H]LTD4 binding in guinea-pig lung. Scatchard analysis of saturation binding data showed a single class of binding sites, with a dissociation constant (KD) of 52.6 +/- 4.9 nM and a density (Bmax) of 30 +/- 12 pmol/mg membrane protein. The binding was inhibited with high affinity by a variety of glutathione-containing leukotriene analogues. Most notable was the inhibition by 1,2,3,4-tetranor LTC4 (Ki = 118 nM) and S-decylglutathione (Ki = 154 nM) since neither of these compounds were contractile agonists on guinea-pig parenchymal strips or guinea-pig ileum nor were they antagonists of LTC4-induced contractions of these smooth muscle preparations. These results indicate that the observed binding of [3H]LTC4 to guinea-pig lung membranes is not to a contractile receptor.
Asunto(s)
Pulmón/metabolismo , SRS-A/metabolismo , Animales , Unión Competitiva , Membrana Celular/metabolismo , Cobayas , Íleon/metabolismo , Técnicas In Vitro , Isomerismo , Cinética , Masculino , Contracción Muscular , Músculo Liso/metabolismoRESUMEN
Rioprostil (2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16-methyl prostaglandin (PG)E1) is a potent orally active inhibitor of gastric acid secretion in both rats and dogs. It prevents gastric lesions in rats induced by ethanol, acetylsalicylic acid, strong acid, strong base, hypertonic saline and thermal injury at doses 100 times less than its antisecretory dose. The cytoprotective effect of rioprostil can be observed when given 4 min before challenge with ethanol and measured 60 min later. The peak antiulcer effect is observed when rioprostil is given 30 min before ethanol challenge and the oral ED50 is 1.93 (1.74-2.15) micrograms/kg. Rioprostil possesses weak PGE-like activity in an isolated tissue cascade, no contragestational activity in rats, hamsters or rabbits, and no remarkable cardiovascular or pulmonary activity in dogs. The animal pharmacology of this compound suggests that it should be useful in the treatment or prophylaxis of peptic ulcer disease and gastric lesions associated with noxious irritants such as ethanol and nonsteroidal antiinflammatory drugs.
Asunto(s)
Antiulcerosos/farmacología , Ácido Gástrico/metabolismo , Prostaglandinas E/farmacología , Úlcera Gástrica/prevención & control , Animales , Cricetinae , Perros , Etanol/farmacología , Femenino , Mucosa Gástrica/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Conejos , Ratas , Rioprostilo , Especificidad de la Especie , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/fisiopatología , Factores de TiempoRESUMEN
The synthesis of prostaglandin analogs incorporating the dimethylphosphono or dimethylphosphonomethyl moiety in place of the carboxylic acid moiety is described. These analogs exhibited only very low levels of smooth muscle activity during biological testing.
Asunto(s)
Prostaglandinas Sintéticas/síntesis química , Animales , Músculo Liso/efectos de los fármacos , Prostaglandinas Sintéticas/farmacologíaAsunto(s)
Prostaglandinas E Sintéticas/síntesis química , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Pollos , Ciclobutanos , Femenino , Jugo Gástrico/metabolismo , Cobayas , Humanos , Técnicas In Vitro , Masculino , Métodos , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Prostaglandinas E Sintéticas/farmacología , Ratas , Contracción Uterina/efectos de los fármacosRESUMEN
The synthesis of prostaglandin analogs incorporating the 3-hydroxycyclohexenyl moiety in place of the natural C13-C20 side-chain has been accomplished via copper-assisted conjugate addition of the cycloalkenyllithium 2 to the cyclopentenous intermediates 4, 7 and 10.