MOLECULAR PHARMACOLOGY, 34:172-179 Potential-Dependent Allosteric Modulation of 1,4-Dihydropyridine Binding by d-(cis)-Diltiazem and (±)-Verapamil in Living Cardiac

We have studied allostenc effects of the Ca channel blockers d-(cis)-diltiazem, (±)-verapamil, and (S)- and (R)-devapamil on the specific binding of the 1,4-dihydropyridine derivative (+)-[3H]PN 200-1 1 0 to intact tissue cultured rat heart cells. In polarized cells (membrane potential,-38 ± 4 my) d-(cis)-diltiazem (5 zM) in-creased the affinity of the radiolabel 2-4-fold causing 100-187% enhancement of binding at (+)-PN 200-1 10 concentrations below 0.5 flM. (±)-Verapamil (0.1-3 M) had a similar, although smaller, effect on (+)-PN 200-1 1 0 binding. The two enantiomers of de-vapamil were without effect. In depolarized cells (membrane potential, 0 mV) d-(cis)-diltiazem had a small and the phenylal-kylamines a strong inhibitory effect on (+)-PN 200-1 1 0 binding, mainly due to a reduction of binding affinity. At 50 % receptor occupation by the radioligand, (R)-devapamil, (±)-verapamil, and (S)-devapamil displaced 40, 55, and 75%, respectively, of spe