Change of Mechanical Activity to Contraction from the Relaxation Induced by the Intracellular Ca²⁺ Antagonist KT-362; Effects of Alkylation of Side Chain, and Substitution of 2, 3, 4, 5-Tetrahydro-1, 5-Benzothiazepine Derivatives

Abstract

KT-362 (5-[3-[2-(3, 4-Dimethoxyphenyl)ethyl]aminopropionyl]-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine fumarate) is an intracellular Ca²⁺ antagonist. The compound obtained by introducing methyl groups onto the nitrogen (R₂) of the side chain of KT-362 showed vasoconstrictive activity. Therefore we synthesized various derivatives, and examined their activities. Substitution at position R₂ 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 R₁ 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 EC₅₀ value of 3.47×10^-8 M for contraction of rabbit iliac artery. The action of compound 9b was antagonized competitively by an H₁-histamine receptor antagonist, diphenhydramine, and the pA₂ value was 7.82. The maximum constriction was inhibited by a Ca²⁺ entry blocker, nicardipine, but not by an α₁-adrenoreceptor antagonist, prazosin. In a Ca²⁺-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.