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

Article abstract of DOI:10.1248/cpb.45.1761

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 two 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- dimethoxyphenyl)ethyl]aminopropionyl}-2,3,4,5-tetrahydro-1,5- benzothiazepine fumarate (9b), showed an EC₅₀ value of 3.47 x 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 observed. Though this phasic constriction was inhibited by diphenhydramine, it was not inhibited by prazosin or nicardipine.

Full text of DOI:10.1248/cpb.45.1761

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