Schramm M, Thomas G, Towart R, Franckowiak G
Nature. 1983;303(5917):535-7. doi: 10.1038/303535a0.
Transmembrane influx of extracellular calcium through specific calcium channels is now accepted to have an important role in the excitation-contraction coupling of cardiac and smooth muscle. The importance of such slow calcium channels has been underlined by the development of specific calcium channel blocking agents, the 'calcium antagonists', typified by verapamil, nifedipine and diltiazem. These drugs have been used to investigate the properties of slow calcium channels in a variety of tissues. We have found that small modifications to the nifedipine molecule produce other dihydropyridine derivatives (see Fig. 1) with effects diametrically opposite to those of the calcium antagonists: cardiac contractility is stimulated and smooth muscle is contracted. These effects are competitively antagonized by nifedipine. Apparently, nifedipine and the novel compounds bind to the same specific dihydropyridine binding sites in or near the calcium channel. In contrast to nifedipine, however, the new compounds promote--instead of inhibiting--the influx of Ca2+ ions. We report here the properties of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate), one of the most potent of these novel compounds.
现在人们普遍认为，细胞外钙通过特定钙通道的跨膜内流在心肌和平滑肌的兴奋-收缩偶联中起着重要作用。维拉帕米、硝苯地平和地尔硫䓬等“钙拮抗剂”这类特异性钙通道阻滞剂的出现，凸显了此类慢钙通道的重要性。这些药物已被用于研究多种组织中慢钙通道的特性。我们发现，对硝苯地平分子进行微小修饰可产生其他二氢吡啶衍生物（见图1），其作用与钙拮抗剂完全相反：刺激心肌收缩力并使平滑肌收缩。这些作用可被硝苯地平竞争性拮抗。显然，硝苯地平和这些新化合物与钙通道内或其附近相同的特异性二氢吡啶结合位点结合。然而，与硝苯地平不同的是，这些新化合物促进而非抑制Ca2+离子内流。我们在此报告BAY K 8644（1,4-二氢-2,6-二甲基-3-硝基-4-(2-三氟甲基苯基)-吡啶-5-羧酸甲酯）的特性，它是这些新化合物中活性最强的之一。
