The interactions of 1,4-dihydropyridines bearing a 2-(2-aminoethylthio)methyl substituent at voltage-dependent Ca2+ channels of smooth muscle, cardiac muscle and neuronal tissues.

The Ca2+ channel antagonistic potencies of tiamdipine [2-(2-aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-6-m ethyl-4-(3- nitrophenyl)-1,4-dihydropyridine] and nifedipine [2,6-dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydrop yri dine] 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. KI values of the corresponding tiamdipine analogs for the inhibition of specific [3H]PN 200-110 [(+)-[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-(2-acetamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy- 6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine, and the four stereoisomers of 2-(2-pyrrolidinylmethylthio)methyl-3-carboethoxy-5-carbom eth oxy-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.(ABSTRACT TRUNCATED AT 250 WORDS)