Change of Mechanical Activity to Contraction from the Relaxation Induced by the Intracellular Ca^<2+> Antagonist KT-362; Effects of Alkylation of Side Chain, and Substitution of 2,3,4,5-Tetrahydro-1,5-Benzothiazepine Derivatives

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KT-362 (5-[3-[2-(3,4-Dimethoxyphenyl)ethyl]aminopropionyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate) is an intracellular Ca^<2+> antagonist. The compound obtained by introducing methyl groups onto the nitrogen (R_2) of the side chain of KT-362 showed vasoconstrictive activity. Therefore we synthesized various derivatives, and examined their activities. Substitution at position R_2 of the side chain resulted in potent contractile activity, and the optimal alkyl length was to or three carbons. The potency was further increased by the introduction of a chloro group at the R_1 position of 2,3,4,5-tetrahydro-1,5-benzothiazepines. One of the synthesized compounds, 8-chloro-5-{N-ethyl-N-[2-(3,4-dimethyoxyphenyl)ethyl]aminopropionyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate (9b), showed an EC_<50> value of 3.47×10^<-8> M for contraction of rabbit iliac artery. The action of compound 9b was antagonized competitively by an H_1-histamine receptor antagonist, diphenhydramine, and the pA_2 value was 7.82. The maximum constriction was inhibited by a Ca^<2+> entry blocker, nicardipine, but not by an α_1-adrenoreceptor antagonist, prazosin. In a Ca^<2+>-free medium, tonic constriction induced by 9b disappeared, and only a phasic constriction was oberved. Though this phasic constriction was inhibited by diphenhydramine, it was not inhibited by prazosin or nicardipine.
公益社団法人日本薬学会の論文
1997-11-15