Cardiovascular effects of substituted tetrahydroisoquinolines in rats

Abstract

A series of substituted tetrahydroisoquinolines derived from the cleavage products of tetrandrine were found to inhibit [3H]‐nitrendipine binding to rat cerebral cortical membranes. Those compounds which displaced [3H]‐nitrendipine binding were also able to inhibit high KCl‐induced contraction of rat aorta in vitro. There was a significant correlation between the ability of these tetrahydroisoquinolines to inhibit [3H]‐nitrendipine binding and KCl‐induced contraction (r = 0.99, P < 0.001). 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 [3H]‐nitrendipine binding site and reduced the apparent affinity but not the maximal number of binding sites in saturation analysis. 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. It is suggested that CPU‐23 may exert its cardiovascular effects via interaction with the dihydropyridine binding site on the L‐type calcium channel. 1992 British Pharmacological Society