CGP-28392

The goal of this study was to estimate: (i) the action of 5-nitro-substituted 1,4-dihydropyridines as well as Bay K 8644 (CAS [71145-03-4]) and CGP 28392 (CAS [89289-93-0]) on cardiac action potential duration (APD) and isometric contraction in the isolated guinea pig papillary muscles; (ii) whether the effects of 2-propoxyethyl 4-(2-difluoromethoxyphe-nyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate on the lengthening of cardiac APD were related to certain potassium channels (e.g., I(K1), K(ATP) and I(K)); and (iii) the modulation of the contraction-relaxation effects on isolated human vena saphena magna samples using three 5-nitro-substituted 1,4-dihydropyridine derivatives, displaying the positive inotropic and AP duration effects.

The experiments were conducted on isolated human vena saphena magna samples and papillary muscles from adult guinea pigs. Isometric contractions and APs were recorded using a force transducer and microelectrode technique, respectively.

2-Propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate significantly increased APD and isometric contractions in a concentration-dependent manner. Its effects were suppressed by dl-sotalol. Other derivatives tested, such as Bay K 8644 and CGP 28392, showed either negligible effects or increased the contraction force but did not influence the APD. Compounds possessing positive inotropic properties at a concentration of 10(-7) to 10(-4) M significantly relaxed the isolated vessel samples pre-contracted with phenylephrine (10(-4) M). The weakest response was shown by 2-propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate.

These results show that 5-nitro-substituted 1,4-dihydropyridine derivatives with positive inotropic action significantly relaxed isolated vein samples that were pre-contracted with phenylephrine in a dose-dependent manner. 2-Propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate prolongs the cardiac APD, which could be determined by the rapid component I(Kr) of the delayed potassium current I(K) blocker.

The discovery that 1,4‐dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine‐type, the so‐called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+‐channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third‐generation 1,4‐dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2‐methyl‐4‐(1‐methyl)‐5‐nitro‐2‐imidazolyl‐5‐oxo‐1,4,5,6,7, 8‐hexahydroquinolin‐3‐arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea‐pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea‐pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure‐activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.