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 alpha 1-adrenoreceptor antagonist, prazosin. In a Ca(2+)-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.