SYNTHESIS AND CALCIUM ANTAGONISTIC ACTIVITY OF L]-5,6,7,8-TETRAHYDROTHIENOL[3,2-B][1,4]THIAZEPINE FUMARATE

KT-362 is an antiarrhythmic and antihypertensive agent with vasodilati ng 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 pro vided -[2-(3,4-dimethoxyphenyl)ethyl]-beta-alanyl]-5,6,7 ,8-tetrahydro thieno [3,2-b][1,4] thiazepine (1). Compound 1 shows a negative chrono tropic activity in spontaneously beating right atria (IC50 = 23 mu M, n = 7), and a negative inotropic effect in papillary muscles (IC50 = 2 ,7 mu M, n = 7) and left atria (IC50 = 4 mu M, n = 6) of the guinea-pi g heart. The decrease of contractility in papillary muscles could be a ntagonized by increasing the extracellular calcium concentration. Comp ound 1 was found to affect high (IC50: 70 +/- 5 mu M) and low (IC50: 1 29 +/- 34 mu M) voltage-activated calcium channel currents as well as voltage-activated sodium channel currents (IC50: 80 +/- 13 mu M) in ch ick dorsal root ganglion neurons. In addition, nicotine-induced curren ts were potently inhibited (IC50: 6 +/- 0.7 mu M) in bovine chromaffin cells.