title: 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.
abstract: 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)
authors.affiliation: Department of Biochemical Pharmacology, School of Pharmacy, State University of New York, Buffalo 14260.
authors.forename: Y W
authors.initials: YW
authors.lastname: Kwon
authors.forename: Q
authors.initials: Q
authors.lastname: Zhong
authors.forename: X Y
authors.initials: XY
authors.lastname: Wei
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.forename: D J
authors.initials: DJ
authors.lastname: Triggle
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D010069:Oxadiazoles / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D004095:Dihydropyridines; D010069:Oxadiazoles; D013876:Thiophenes; C010354:tiamenidine; D009543:Nifedipine; D011188:Potassium; D017275:Isradipine