The coronary vasodilating action of 1,5-benzothiazepine derivatives and the structureactivity relationship were examined in the anesthetized dog. 2-(4-Methoxyphenyl), 3-acyloxy or alkyloxy, 5-dimethylaminoethyl and 7-hydrogen moieties were important for vasodilation.The action of the derivatives was found to be stereospecific for the d-cis-isomer.Based on these findings, it can be concluded that d-3-acetoxy-cis-2,3-(5H) -one hydrochloride (CRD-401) was the most potent compound among the derivatives tested. The metabolites of dl-isomer of CRD-401, i.e. deacetyl and deacetyl-O-or N-demethyl compounds, were less active and less toxic than the parent compound.

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Abstract-Diltiazem, a new 1,5-benzothiazepine derivative, antagonized calcium ion and thus caused a reduction in the contractile force of isolated papillary muscle. The antagonistic ratio of diltiazem to calcium ion was estimated to be approx. 1 : 100. A lower concentration of diltiazem (2.2 yX 10-13 M) decreased the contractile force without affecting significantly the intracellularly recorded resting and action potentials. When the concentration of the compound was increased to 2.2 x 10-5 M, only the maximum rate of rise of the action potential was reduced, while the other parameters of the ac tion potential were also affected at 1

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In a previous report (1), it was shown that a new 1, 5-benzothiazepine derivative, 3-acetoxy-2, 3-dihydro-5-[2-(diethylamino) ethyl]-2-(p-methoxyphenyl)-1, 5-benzothiazepine-4 (5H)-one hydrochloride, produced a potent coronary vasodilator effect in anesthetized dogs. Among four stereoisomers of the compound, d-and l-isomers of cis-and trans forms, the d-cis-isomer (CRD-401) exhibited the most powerful effect when injected into the femoral vein. Without increase in myocardial oxygen consumption, a significant in crease in coronary blood flow resulted.
The present report deals with the vasodilator action of d-cis-isomer of the new ben zothiazepine derivative under the influence of various pharmacological blockers. The results are considered in relation to the mechanism of the compound. Effects of dl-and l-cisisomers and dl-trans-isomer were also investigated and compared with the action of d-cis-isomer. Experiments were performed on the coronary and femoral arteries in anes thetized dogs and on the coronary vessels in isolated hearts of the guinea pig. MATERIALSAND METHODS Coronary artery blood flowMale dogs weighing 15-25 kg were anesthetized using sodium pentobarbital (30 mg/ kg, i.v.) and the chest was opened by the removal of a portion of the left fourth rib under positive pressure respiration (room air). According to the method of Eckenhoff et al. (2), the blood from the left carotid artery was led to the anterior descending coronary artery by a short extracorporeal loop. The blood fow was then measured by means of an electro magnetic flowmeter (Nihon Koden, MF-2), which was introduced into the loop. Femoral arterial pressure was obtained and recorded via a pressure transducer as well as the coronary blood flow into a multipurpose polygraph (Nihon Koden, RM-150). Femoral artery blood flowMale dogs (10-14 kg) were anesthetized using sodium pentobarbital (30 mg/kg, i.v.).A short extracorporeal loop was introduced into the left femoral artery and the blood flow was measured by the same procedure described above. The test compound, in a volume not exceeding 0.5 ml, was injected into the extracorpo