Ca2+ channel antagonists
Springer Online Journal Archives 1860-2000
Summary The Ca2+ channel antagonistic potencies of tiamdipine [2-(2-aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine] and nifedipine [2,6-dimethyl-3,5-dicarbomethoxy-4-(2nitrophenyl)-1,4-dihydropyridine] analogs bearing phenyl ring substituents were studied using pharmacologic and radioligand binding techniques. Additionally, analogs of tiamdipine possessing (2-aminoethylthio)methyl-, (2-acetamidoethylthio)methyl-and (2-pyrrolidinylmethylthio)methyl-groups at the C2 position of the 1,4-dihydropyridine ring have been studied. Tiamdipine and nifedipine analogs inhibited K+-induced contractile responses in rat tail artery. IC50 values of 4-phenyl ring substituted 2-(2-aminoethylthio)methyl tiamdipine analogs ranged from 10−7 mol/l to 10−8 mol/l. However, the corresponding 4-phenyl ring substituted nifedipine analogs covered a wider range of potency from 10−6 mol/l to 10−9 mol/l. K, values of the corresponding tiamdipine analogs for the inhibition of specific [3H]PN 200-110 [( I- ) [3H]isopropyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate] binding-ranged from 10−7 mol/l to 10−9 mol/l in guinea pig ileal and rat heart membranes and rat brain synaptosomes. The two stereoisomers of tiamdipine and its analog 2-(2acetamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine, and the four stereoisomers of 2-(2-pyrrolidinylmethylthio)methyl-3carboethoxy-5-carbomethoxy-6-methyl-4-(3-nitrophenyl)1,4-dihydropyridine showed high stereoselectivity ratios of approximately (−)/(+) = 100 and 1000 in pharmacologic and binding experiments, respectively. The inhibitory actions of 2-(2-aminoethylthio)methyltiamdipine analogs against K+-induced contractile responses in rat tail artery developed very slowly requiring at least 2 h for maximum effect. The recoveries of response to K+ depolarization were also correspondingly slow. However, recovery was greatly accelerated by the presence of the 1,4-dihydropyridine activator Bay K 8644 [2,6-dimethyl-3carbomethoxy-5-nitro-4-(2-trifluoromethyl)-1,4-dihydropyridine, 5 × 10−6 mol/l] immediately prior to the K+ challenge. The 2-(2-acetamidoethylthio)methyl tiamdipine derivative and nifedipine produced maximum inhibitory effects within 10 min, and responses recovered rapidly upon washing. The slow kinetics of onset and offset of action of the tiamdipine analogs and the reduced effects of 4-phenyl substitution relative to agents of the nifedipine series suggest that these two series of 1,4-dihydropyridines exhibit different modes of interaction with the Ca2+ channel. At least part of this difference is to be attributed to the presence of a charged group in the basic tiamdipine series. Trapping of these agents within the membrane phase likely contributes to their observed slow kinetics of action.
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