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

The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,12-hexahydro-6,3- dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-sub stituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolined iones, was evaluated in spontaneously beating and in electrically driv en atria from reserpine-treated guinea pigs. Their effects were compar ed with those induced by amrinone and milrinone in both the atria prep arations. Compounds SF28 1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonit rile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were t he most effective positive inotropic agents. An inhibition of the nega tive influence exerted by endogenous adenosine on heart preparations s eems to be involved in their contractile activity. SF38 (3-benzoyl-2-p henyl-6(1H)-pyridinone), on the contrary, reduced the contractile forc e and the frequency rate of guinea pig atria with a mechanism not rela ted 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 re ceptor pockets according to the resulting inotropic effect.