A unitary mechanism of calcium antagonist drug action

[³H]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, cinnarizine, and prenylamine all reduce [³H]nitrendipine binding affinity. By contrast, diltiazem, a benzothiazepine calcium channel antagonist, 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 prenylamine, lidoflazine, or tiapamil is reversed by D-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 regulating [³H]nitrendipine binding should be calcium antagonists is confirmed by calcium antagonism in guinea pig ileum observed with the antihistamine dimethindene, the neuroleptics thioridazine and mesoridazine, and the anticholinergic biperiden.