INTERACTION OF CALCIUM-CHANNEL ANTAGONISTS WITH CALCIUM - STRUCTURAL STUDIES ON NICARDIPINE AND ITS CA2+ COMPLEX
INTERACTION OF CALCIUM-CHANNEL ANTAGONISTS WITH CALCIUM - STRUCTURAL STUDIES ON NICARDIPINE AND ITS CA2+ COMPLEX
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DOI：
10.1021/jm00051a017
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发表时间：
1994-12-09
影响因子：
7.3
通讯作者：
ANANTHANARAYANAN, VS
中科院分区：
文献类型：
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作者：
BELCIUG, MP;ANANTHANARAYANAN, VS
用一维核磁共振和差示吸收光谱技术研究了尼卡地平在乙腈中的构象特征。数据表明，在乙腈溶液中，尼卡地平的反周面形式占主导地位。向药物溶液中加入Ca 2+引起200-400 nm区域的差异吸收光谱和其许多H-1和C-13 NMR共振的显著变化。变化是最显着的比例为0.5 Ca 2+：药物。结合数据的分析表明，主要种类是2：1的药物：Ca 2+“三明治"复合物，估计解离常数为100 μ M，在25 ℃。一维核Overhauser效应（NOE）的实验显示，通过空间连接的药物之前和之后的钙离子结合。这些变化与H-1和C-13化学位移的变化一起表明，在Ca 2+存在下，吡啶部分的4-芳基环取代基更靠近C3-侧链。这种吸引力是通过芳基的m-NO2中的氧原子和二氢吡啶环侧链中的COOCH 2基团螯合Ca 2+离子来实现的，并产生稳定的同平面构象。这种构象的偏好也观察到在硝苯地平在乙腈中的Ca 2+复合物推断从相当有限的NOE数据获得。我们的研究提供了一个详细的尼卡地平的解决方案的结构，也导致了一个建议的作用，Ca 2+的行动，这可能是其他二氢吡啶。
Conformational features of nicardipine in acetonitrile, in the absence and presence of Ca2+ were investigated by one-dimensional NMR and difference absorption spectroscopy techniques. The data show that in acetonitrile solution the antiperiplanar form of nicardipine is dominant. The addition of Ca2+ to the drug solution caused marked changes in the difference absorbance spectra in the 200-400 nm region and in many of its H-1 and C-13 NMR resonances. The changes were most significant up to a ratio of 0.5 Ca2+:drug. Analysis of the binding data showed the predominant species to be a 2:1 drug:Ca2+ ''sandwich'' complex with an estimated dissociation constant-of 100 mu M at 25 degrees C. One-dimensional nuclear Overhauser effect (NOE) experiments revealed through-space connectivities in the drug before and after Ca2+ binding. These changes in conjunction with the changes in H-1 and C-13 chemical shifts suggest a structure in which the 4-aryl ring substituent of the pyridine moiety moves closer to the C3-side chain in the presence of Ca2+. This attraction is achieved via the chelation of the Ca2+ ion by the oxygen atoms in the m-NO2 of the aryl group and the COOCH2 group in the side chain of the dihydropyridine ring, and gives rise to a stable synperiplanar conformation. A preference for this conformation was also observed in the Ca2+ complex of nifedipine in acetonitrile as inferred from the rather limited NOE data obtained. Our study provides a detailed solution structure for nicardipine and also leads to a suggestion of a role for Ca2+ in the action of this and possibly other dihydropyridines.