In vitro comparative studies of the calcium-entry activators YC-170, CGP 28392, and BAY K 8644.
Recently, the novel dihydropyridine derivates YC-170, CGP 28392, and BAY K 8644 have been reported to act in the opposite way to Ca2+-entry blockers. We have found that these compounds inhibit the binding of [3H]nitrendipine on guinea pig heart membranes (Ki: 6 nM BAY K 8644, 115 nM CGP 28392 and 690 nM YC-170). Like those of nifedipine (Ki 1 nM), the curves had slopes close to unity, and, unlike those of some nondihydropryridine Ca2+ antagonists, were not altered in the presence of diltiazem, indicating a competitive interaction at dihydropyridine-sensitive sites. In isolated guinea pig atria, these agents exerted positively inotropic effects similar in their potency ratio to those observed in the binding experiments (BAY K 8644 1, CGP 28392 1:17, YC-170 1:600). The maximum inotropic effects of BAY K 8644 and CGP 28392, and of YC-170 corresponded respectively to two-thirds and one-third of those induced by isoprenaline or extracellular Ca2+. In the isolated rat mesenteric artery, perfused with a depolarizing solution, vasoconstrictor Ca2+ dose-response curves are shifted to the right by nifedipine. By contrast, BAY K 8644 and CGP 28392 caused a distinct leftward shift of the Ca2+ dose-response curves, at concentrations of 3-300 nM and 30-300 nM, respectively, and YC-170 a marginal shift at concentrations of 200-2000 nM, i.e., similar ranges to their inhibitory effects on [3H]nitrendipine binding. At higher concentrations, all three compounds produced Ca2+-antagonistic effects. These results indicate that the compounds act at dihydropyridine-sensitive sites and exert partial agonistic activities in vascular and myocardial tissue.
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D008643:Mesentery / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009568:Nitrendipine; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects
D007473:Ion Channels; D011725:Pyridines; C046721:YC 170; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C040525:CGP 28392; D009568:Nitrendipine; D009543:Nifedipine; D002118:Calcium