Synthesis and Calcium Antagonistic Activity of 8-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-β-alanyl]-5,6,7,8-tetrahydrothieno[3,2-b][1,4]thiazepine Fumarate

KT-362 is an antiarrhythmic and antihypertensive agent with vasodilating activity. Since it carries a homoveratryl group in the side chain, an obvious relation exists to the verapamil-type calcium antagonists. Replacement of the fused aromatic moiety in KT-362 with thiophene provided 8-N-2-(3,4-dimethoxyphenyl)ethyl]-β-analyl]-5,6,7,8-tetrahydrothieno3,2-b]1,4] thiazepine ( 1 ). Compound 1 shows a negative chronotropic activity in spontaneously beating right atria (IC₅₀ = 23 μM, n = 7), and a negative inotropic effect in papillary muscles (IC₅₀ = 2.7 μM, n = 7) and left atria (IC₅₀ = 4 μM, n = 6) of the guinea-pig heart. The decrease of contractility in papillary muscles could be antagonized by increasing the extracellular calcium concentration. Compound 1 was found to affect high (IC₅₀: 70 ± 5 μM) and low (IC₅₀: 129 ± 34 μM) voltage-activated calcium channel currents as well as voltage-activated sodium channel currents (IC₅₀: 80 ± 13 μM) in chick dorsal root ganglion neurons. In addition, nicotine-induced currents were potently inhibited (IC₅₀: 6 ± 0.7 μM) in bovine chromaffin cells.