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‐tetrahydrothieno[3,2‐ b ][1,4] thiazepine ( 1 ). Compound 1 shows a negative chronotropic activity in spontaneously beating right atria (IC 50 = 23 μM, n = 7), and a negative inotropic effect in papillary muscles (IC 50 = 2.7 μM, n = 7) and left atria (IC 50 = 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 (IC 50 : 70 ± 5 μM) and low (IC 50 : 129 ± 34 μM) voltage‐activated calcium channel currents as well as voltage‐activated sodium channel currents (IC 50 : 80 ± 13 μM) in chick dorsal root ganglion neurons. In addition, nicotine‐induced currents were potently inhibited (IC 50 : 6 ± 0.7 μM) in bovine chromaffin cells.