The interaction of felodipine with calcium-binding proteins.
The interaction of felodipine with calcium-binding proteins.
复制标题
非洛地平与钙结合蛋白的相互作用。
DOI：
10.1097/00005344-198710001-00010
复制
发表时间：
1987
影响因子：
3
通讯作者：
Mills,JS
中科院分区：
文献类型：
--
作者：
Johnson,JD;Andrews,CT;Khabbaza,EJ;Mills,JS
非洛地平在二氢吡啶类钙拮抗剂中是独一无二的，因为它对放松猪冠状动脉最有效（ic50 = 1.5× 10−10 M）；它不像硝苯地平和尼索地平那样对光灭活敏感，而且是荧光的。非洛地平的荧光使我们能够研究其与肌肉中各种钙结合蛋白相互作用的许多方面，包括钙调蛋白、骨骼肌钙蛋白C和心脏肌钙蛋白C。钙与这些蛋白质上钙特异性调节位点的结合暴露了变构相关的非洛地平结合位点。其他钙调素拮抗剂和钙拮抗剂（包括丙烯胺、R24571和地尔硫齐）与这些钙结合蛋白的结合消除了两个非洛地平结合位点之间的协同作用，导致非洛地平以20 - 25倍的亲和力与剩余位点结合。此外，高亲和力药物与这些钙结合蛋白上的钙依赖性疏水位点的结合，使其对钙的亲和力显著增加（40 - 50倍）。非洛地平对这些钙结合蛋白的亲和力比非洛地平对冠状动脉舒张的ic50低100 - 1000倍，表明这些钙结合蛋白可能不是非洛地平的主要受体。二氢吡啶与钙通道的结合与这些钙结合蛋白之间的相似性使我们认为，钙通道上的“钙调素样”钙结合蛋白是二氢吡啶钙通道拮抗剂的实际药理受体。通道的这种“钙调素样”成分可以解释钙依赖性结合和钙拮抗剂之间的变构相互作用，这些作用已被报道发生在钙通道上。此外，对钙结合蛋白之间相似性的研究使我们能够假设这些通道阻滞剂如何抑制钙通过钙通道流入。
Felodipine is unique among the dihydropyridine calcium antagonists in that it is the most potent in relaxing porcine coronary arteries (IC 50= 1.5× 10− 10 M); it is not as sensitive to photoinactivation as nifedipine and nisoldipine, and it is fluorescent. The fluorescence of felodipine has allowed us to study many aspects of its interaction with various calcium-binding proteins in muscle, including calmodulin, skeletal troponin C, and cardiac troponin C. Calcium binding to the calcium-specific regulatory sites on these proteins exposes allosterically related felodipine-binding sites. The binding of other calmodulin antagonists and calcium antagonists, including prenylamine, R24571, and diltiazem, to these calcium-binding proteins abolishes the cooperativity between two felodipine-binding sites, resulting in felodipine binding to the remaining site with a 20–25-fold greater affinity. In addition, the binding of high-affinity drugs to these calcium-dependent hydrophobic sites on these calcium-binding proteins produces dramatic increases (40–50-fold) in their affinity for calcium. The affinity of felodipine for these calcium-binding proteins is 100–1,000 times lower than felodipine's IC 50 for relaxing tension in coronary arteries, indicating that these calcium-binding proteins are probably not the primary receptors for felodipine. Similarities between the binding of dihydropyridines to the calcium channel and to these calcium-binding proteins have led us to suggest that a “calmodulin-like” calcium-binding protein on the calcium channel is the actual pharmacological receptor for dihydropyridine calcium channel antagonists. This “calmodulin-like” component of the channel could explain the calcium-dependent binding and allosteric interactions among calcium antagonists that have been reported to occur on the calcium channel. Further, studies of the similarities among calcium-binding proteins have allowed us to hypothesize as to how these channel blockers might act to inhibit calcium influx through calcium channels.