RESUMEN
1. Analgesic activities of N-cyclopropylmethyl derivatives of (-)-6 beta-acetylthionormorphine, KT-89 and KT-90 and their interactions with opioid receptors were studied. 2. KT-89 and KT-90, as well as morphine inhibited the twitch response of the guinea-pig ileal preparation to electrical stimulation. Their pD2 values indicated that KT-89 and KT-90 are about 6.5 and 10 times as potent as morphine, respectively. In guinea-pig ileal preparation KT-89 and KT-90 also behaved as a mu-antagonist. 3. In rabbit vas deferens which contains kappa-receptors, these substances inhibited the twitch response to electrical stimulation and were about 6 times as potent as dynorphin. 4. Their effects on specific binding of [3H]naloxone (mu-selective ligand), [3H]ethylketocyclazocine (kappa-selective ligand) and [3H]D-Ala2-D-Leu5-enkephalin (delta-selective ligand) to the synaptosomal fractions from rat brain were tested. Though both drugs had a nonselectively high affinity to mu-, kappa- and delta-receptors, affinities of KT-89 and KT-90 to kappa-receptors were about 6 and 13 times higher than that of morphine, respectively. 5. Analgesic activities of KT-89 and KT-90 were 6 and 10 times as potent as morphine in an acetic acid-induced writhing test, and 4 and 5 times as potent in a pressure test. 6. The present results suggest that KT-89 and KT-90 induced analgesic actions are mediated through an activation of kappa-receptors. Both the drugs acted as delta-receptor antagonists. Further experiments are needed to study effects of their property as a delta-antagonist on analgesic action.
Asunto(s)
Analgésicos/farmacología , Derivados de la Morfina/farmacología , Receptores Opioides/efectos de los fármacos , Animales , Encéfalo/metabolismo , Encefalina Leucina/antagonistas & inhibidores , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos , Morfina/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Naloxona/farmacología , Dimensión del Dolor , Conejos , Ratas , Ratas Endogámicas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Conducto Deferente/efectos de los fármacosRESUMEN
1. The effect of KC-404, a new antiplatelet and cerebrovasodilating drug, on prostacyclin (PGI2)-induced accumulation of cyclic AMP was investigated using washed platelets of rat. 2. PGI2 enhanced the cyclic AMP content in a concentration-dependent manner. 3. KC-404 at a relatively high concentrations (above 4.34 microM) significantly increased the maximum cyclic AMP accumulation induced by PGI2, without change in its sensitivity. 4. It is concluded that KC-404 potentiates a mechanism of action of PGI2, and a possible relevance of KC-404 for the treatment of cerebrovascular disorders with a tendency of accompanying thromboembolism is suggested.
Asunto(s)
Plaquetas/metabolismo , AMP Cíclico/sangre , Epoprostenol/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Piridinas/farmacología , Vasodilatadores/farmacología , Animales , Plaquetas/efectos de los fármacos , Sinergismo Farmacológico , Técnicas In Vitro , Masculino , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Some pharmacological properties of a newly synthesized morphine derivative, (-)-6 beta-acetylthiomorphine (AcS-morphine) were studied. AcS-morphine was about twice as potent as morphine in the inhibitory action of the twitch response of the guinea-pig ileal preparation to electrical stimulation. AcS-morphine, however, was 5 times as potent as morphine in the analgesic action in the rats. Both the effects of AcS-morphine were inhibited by naloxone, suggesting that the site of action of AcS-morphine is mu-receptors. It is interesting that 6 beta-isomer of AcS-morphine is 5 times as potent as 6 alpha-OH isomer of morphine in the analgesic action, because 6 alpha-OH isomer of morphine is much more potent than that of 6 beta-OH isomer. The effects of AcS-morphine on the specific binding of [3H]-naloxone, [3H]-ethylketocyclazocine and [3H]-D-Ala2-D-Leu5-enkephalin to the membrane fractions from the rat brain were tested. AcS-morphine was about 5 times as potent as morphine in its interactions with opioid receptors, as determined by the binding assay. AcS-morphine, as well as morphine, had a selectively high affinity to mu-receptors. The "sodium effect" and the "GTP effect" of AcS-morphine were almost the same as those of morphine. The dependence liability of AcS-morphine was preliminary tested in the guinea-pig ileal preparations treated with a high concentration of AcS-morphine for 24 hr. Results suggested that AcS-morphine is weaker than morphine in its dependence liability, though it seems almost certain that AcS-morphine does have this liability.