A pharmacological, crystallographic, and quantum chemical study of new inotropic agents

• Published in: Journal of medicinal chemistry Vol. 36; no. 17; pp. 2475 - 2484
• Main Authors: Dorigo, P, Gaion, R. M, Belluco, P, Fraccarollo, D, Maragno, I, Bombieri, G, Benetollo, F, Mosti, L, Orsini, F
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 20-08-1993
• Subjects: Amrinone - chemistry; Amrinone - pharmacology; Animals; Biological and medical sciences; Cardiotonic agents; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacology; Cardiovascular system; Crystallography; Electric Stimulation; Guinea Pigs; Male; Medical sciences; Milrinone; Models, Molecular; Molecular Conformation; Myocardial Contraction - drug effects; Pharmacology. Drug treatments; Pyridones - chemistry; Pyridones - pharmacology; Structure-Activity Relationship; Heart; Atrium; Cardiotonic agent; Rodentia; Contractility; In vitro; Biological activity; Vertebrata; Mammalia; Guinea pig; Structure activity relation; Analog; Animal; Molecular model; Mechanism of action; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00069a005

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 address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.