Floreani M, Borea P A, Gessi S, Mosti L, Fossa P, Dorigo P
Department of Pharmacology, University of Padova, Padova, Italy.
J Pharmacol Exp Ther. 1997 Nov;283(2):541-7.
In electrically driven left atria isolated from guinea pig and rat, a new milrinone analog, 6-ethyl-5-propionyl-1,2-dihydro-2-oxo-3-pyridine carbonitrile, produced a positive inotropic effect that was not dependent on adrenergic mechanisms and was more marked than that exerted by the parent compound. Its inotropic action was almost completely abolished by pretreatment of atria with adenosine deaminase and correlated well with its binding ability to the cardiac adenosine A1 receptor. In this regard, the analog showed a 100-fold higher affinity for adenosine receptor than that of milrinone. Moreover, it shifted to the right the concentration-response curves for the negative inotropic action of the stable adenosine receptor agonist R-phenylisopropyladenosine. The new analog behaved as a competitive inhibitor of Type III phosphodiesterase isolated from both guinea pig and rat, although its Ki value was 10 times higher than that of milrinone. However, an increase in cAMP levels does not seem to be involved in the mechanism of action of the new compound, because the presence of carbachol did not decrease the extent of the positive inotropic effect of the analog and did not modify its EC50 in either guinea pig or rat myocardial preparations. Taken together, these results suggest that the milrinone structure can be modified, giving rise to a more active compound whose inotropic effect in both guinea pig and rat appears to be more clearly related to antagonism toward endogenous adenosine than to Type III phosphodiesterase inhibition.
在从豚鼠和大鼠分离出的电驱动左心房中，一种新型米力农类似物6-乙基-5-丙酰基-1,2-二氢-2-氧代-3-吡啶甲腈产生了正性肌力作用，该作用不依赖于肾上腺素能机制，且比母体化合物所产生的作用更为显著。用腺苷脱氨酶预处理心房后，其正性肌力作用几乎完全消失，并且与其与心脏腺苷A1受体的结合能力密切相关。在这方面，该类似物对腺苷受体的亲和力比米力农高100倍。此外，它使稳定的腺苷受体激动剂R-苯异丙基腺苷的负性肌力作用的浓度-反应曲线向右移动。尽管其Ki值比米力农高10倍，但这种新型类似物对从豚鼠和大鼠分离出的III型磷酸二酯酶表现为竞争性抑制剂。然而，新化合物的作用机制似乎不涉及cAMP水平的升高，因为在豚鼠或大鼠心肌制剂中，卡巴胆碱的存在既没有降低该类似物正性肌力作用的程度，也没有改变其EC50。综上所述，这些结果表明，米力农的结构可以被修饰，从而产生一种活性更高的化合物，其在豚鼠和大鼠中的正性肌力作用似乎更明显地与对内源性腺苷的拮抗作用有关，而不是与III型磷酸二酯酶抑制作用有关。
