A unitary mechanism of calcium ai (dihydropyridine/nifedipine/verapamil/neuroleptic/diltiazem)

H)Nitrendipine binding to drug.receptor sites associated with calcium channels is allosterically regulated by a diverse group of calcium channel antagonists. Verapamil, D-600 (methoxyverapamil), tiapamil, lidoflazine, flunarizine, cinnari- zine, and prenylamine all reduce (3H)nitrendipine binding affin- ity. By contrast, diltiazem, a benzothiazepine calcium channel an- tagonist, enhances (3H)nitrendipine binding. All these drug effects involve a single site allosterically linked to the (3H)nitrendipine binding site. Inhibition of (3H)nitrendipine binding by prenyl- amine, lidoflazine, or tiapamil is reversed byD-600 and diltiazem, which alone respectively slightly reduce or enhance (3H)nitrendipine binding. Diltiazem reverses the inhibition of (3H)nitrendipine binding by D-600. Our prediction that drugs allosterically regu- lating (3H)nitrendipine binding should be calcium antagonists is confirmed by calcium antagonism in guinea pig ileum observed with the antihistamine dimethindene, the neuroleptics thiorida- zine and mesoridazine, and the anticholinergic biperiden.