A Unitary Mechanism of Calcium Antagonist Drug Action

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 80; no. 3; pp. 860 - 864
• Main Authors: Kenneth M. M. Murphy, Gould, Robert J., Largent, Brian L., Snyder, Solomon H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.02.1983; National Acad Sciences
• Subjects: Amines; Antiallergics; Antipsychotic agents; Binding, Competitive; Calcium; Calcium Channel Blockers - classification; Calcium Channel Blockers - metabolism; Calcium channels; Dihydropyridines; Ileum; Ileum - metabolism; Kinetics; Nifedipine - analogs & derivatives; Nifedipine - metabolism; Nitrendipine; Pharmacology; Receptors; Zines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.80.3.860

[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.