CARDIOVASCULAR EFFECTS OF SUBSTITUTED TETRAHYDROISOQUINOLINES IN RATS

1 A series of substituted tetrahydroisoquinolines derived from the cleavage products of tetrandrine were found to inhibit [H-3]-nitrendipine binding to rat cerebral cortical membranes. Those compounds which displaced [H-3]-nitrendipine binding were also able to inhibit high KCl-induced contraction of rat aorta in vitro. 2 There was a significant correlation between the ability of these tetrahydroisoquinolines to inhibit [H-3]-nitrendipine binding and KCl-induced contraction (rb = 0.99, P < 0.001). 3 CPU-23 (1-{1-[(6-methoxy)-naphth-2-yl]}-propyl-2-(1-piperidine)-acetyl-6,7-dimethoxy-1,2,3,4,-tetrahydroisoquinoline), one of the most potent compounds identified in this series, behaved as a simple competitive inhibitor at the [H-3]-nitrendipine binding site and reduced the apparent affinity but not the maximal number of binding sites in saturation analysis. 4 In contrast to nifedipine which caused hypotension and tachycardia, CPU-23 induced both hypotension and bradycardia in a dose-dependent manner in pentobarbitone-anaesthetized Sprague-Dawley rats, spontaneously hypertensive and age-matched normotensive WKY rats. 5 It is suggested that CPU-23 may exert its cardiovascular effects via interaction with the dihydropyridine binding site on the L-type calcium channel.