A PHARMACOLOGICAL, CRYSTALLOGRAPHIC, AND QUANTUM-CHEMICAL STUDY OF NEW INOTROPIC AGENTS

被引:54
作者
DORIGO, P
GAION, RM
BELLUCO, P
FRACCAROLLO, D
MARAGNO, I
BOMBIERI, G
BENETOLLO, F
MOSTI, L
ORSINI, F
机构
[1] UNIV MILAN,INST PHARMACEUT CHEM,I-20131 MILAN,ITALY
[2] CNR,CTR STUDIO SOSTANZE ORGAN NAT,I-16132 GENOA,ITALY
[3] UNIV GENOA,INST PHARMACEUT SCI,I-16132 GENOA,ITALY
[4] CNR,INST CHEM & TECHNOL RADIOELEMENTS,I-35100 PADUA,ITALY
关键词
D O I
10.1021/jm00069a005
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may adress the different molecules toward distinct receptor pockets according to the resulting inotropic effect.
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页码:2475 / 2484
页数:10
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