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 af...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1983-02, Vol.80 (3), p.860-864
Main Authors: Kenneth M. M. Murphy, Gould, Robert J., Largent, Brian L., Snyder, Solomon H.
Format: Article
Language:English
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
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Summary:[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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.80.3.860