钙拮抗剂药物作用的单一机制。
A unitary mechanism of calcium antagonist drug action.
作者信息
Murphy K M, Gould R J, Largent B L, Snyder S H
出版信息
Proc Natl Acad Sci U S A. 1983 Feb;80(3):860-4. 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.
[3H]尼群地平与钙通道相关的药物受体位点的结合受到多种钙通道拮抗剂的变构调节。维拉帕米、D - 600（甲氧基维拉帕米）、替帕米、利多氟嗪、氟桂利嗪、桂利嗪和普尼拉明均降低[3H]尼群地平的结合亲和力。相比之下，苯并硫氮䓬类钙通道拮抗剂地尔硫䓬则增强[3H]尼群地平的结合。所有这些药物效应都涉及一个与[3H]尼群地平结合位点变构相连的单一部位。普尼拉明、利多氟嗪或替帕米对[3H]尼群地平结合的抑制作用可被D - 600和地尔硫䓬逆转，而D - 600和地尔硫䓬单独作用时分别会轻微降低或增强[3H]尼群地平的结合。地尔硫䓬可逆转D - 600对[3H]尼群地平结合的抑制作用。我们的预测，即变构调节[3H]尼群地平结合的药物应为钙拮抗剂，已通过组胺二甲茚定、抗精神病药物硫利达嗪和甲砜达嗪以及抗胆碱能药物比哌立登在豚鼠回肠中观察到的钙拮抗作用得到证实。
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