o-Isothiocyanate dihydropyridine (oNCS-DHP), a long-acting, reversible inhibitor of the Ca++ channel.
The binding characteristics and pharmacological properties of o-isothiocyanate dihydropyridine [oNCS-DHP; 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-isothiocyanatophenyl)-1, 4-dihydropyridine] were investigated in guinea pig heart and ileum. [3H]oNCS-DHP bound to a single population of high-affinity sites (Bmax = 107 fmol/mg of protein and Kd = 0.99 nM) in cardiac membranes, with a specificity characteristic of dihydropyridine receptors. After incubation of membranes with the tracer (0.5 nM), addition of excess nifedipine (1 microM) caused a dissociation of [3H]oNCS-DHP from its binding site. The reversibility of [3H]oNCS-DHP binding was confirmed by the lack of affinity labeling of cardiac membranes as determined by sodium dodecylsulfate-polyacrylamide gel electrophoresis. oNCS-DHP inhibited the inward Ca++ current of isolated guinea pig cardiac myocytes as determined in voltage-clamp experiments. In isolated perfused guinea pig hearts, oNCS-DHP caused a concentration-dependent increase in coronary artery flow and a decrease in left ventricular pressure. The effects of the highest concentration (0.3 microM) were still near maximal after a 1-h washout. Suppression of K+ depolarization-induced contractures of isolated ileal longitudinal muscle strips by oNCS-DHP remained maximal even after 5 h of washout. In all of the three biological test systems investigated, the Ca++ channel activator Bay K 8644 caused a complete and rapid reversal of the inhibitory effects of oNCS-DHP. Thus, it can be concluded that oNCS-DHP does not bind irreversibly to Ca++ channel dihydropyridine receptors in guinea pig heart and ileum. However, the o-isothiocyanatophenyl substituent on the dihydropyridine molecule confers upon the compound a very long duration of Ca++ channel blocking activity.
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D004095:Dihydropyridines; D004355:Drug Stability; D004591:Electrophoresis, Polyacrylamide Gel; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D017879:Isothiocyanates; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014316:Tritium
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D017879:Isothiocyanates; D014316:Tritium; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C045531:2,6-dimethyl-3,5-dicarbomethoxy-4-(2-isothiocyano)phenyl-1,4-dihydropyridine; D009543:Nifedipine; D002118:Calcium