Synthesis and in vitro dual calcium channel antagonist-agonist activity of some 1, 4-Dihydo-2,6-dimethyl-3-nitro and cyano-4-(1-methyl-5- nitro-1H-imidazol-2-yl)-5-pyridinecarboxylates

Background and purpose of the study: The vasorelaxant action of the dihydropyridines(DHPs) provides many useful clinical indications. However, their negative effects oncardiac contractility is still of a great concern especially in patients with heart failure.Design and synthesis of dual action compounds, i. e. smooth muscle calcium channelantagonist/cardiac muscle calcium channel agonist provides better and safer compoundsparticularly in patients with compromised cardiac contractility. In the present study, dualcardioselective Ca2+ channel agonists / vascular selective smooth muscle Ca2+ channelantagonists as third generation of DHP drugs were synthesized by a reported method.Methods: Synthetic procedure involved condensation of isopropyl-3-aminocrotonate withnitroacetone and 1-methyl-5-nitroimidazole2-carboxaldehyde and condensation ofalkylacetoacetates with 3-aminocrotonitryl and 1-methyl-5-nitro-1H-imidazole-2-carbaldehyde for the preparation of 1,4-Dihydo-2,6-dimethyl-3-nitro and cyano-4-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-pyridinecarboxylates, respectively. The in vitro effectsof the synthesized compounds were evaluated on longitudal Smooth Muscle (GPILSM) andGuinea Pig Left Atrium (GPLA) preparations and finally, their conformations andstructure-activity relationships were assessed.Results and major conclusion: All compounds showed calcium channel antagonist activityon isolated guinea pig ileum and some of them showed calcium channel agonist effects (orpositive inotropic effect instead of calcium channel agonist effect) on isolated guinea-pigleft atrium. QSAR and conformational analyses showed that conformation and charge ofaryl substituents at C4 position have a main role in antagonistic activity while carbonylgroup at C5 position plays an important role in agonistic effects.