Belciug M P, Ananthanarayanan V S
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
J Med Chem. 1994 Dec 9;37(25):4392-9. doi: 10.1021/jm00051a017.
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 1H and 13C 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 microM 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 1H and 13C chemical shifts suggest a structure in which the 4-aryl ring substitute 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.
采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、有无Ca2+存在时的构象特征。数据表明，在乙腈溶液中，尼卡地平的反式平面构象占主导。向药物溶液中加入Ca2+会导致200 - 400 nm区域的差示吸收光谱及其许多1H和13C核磁共振共振发生显著变化。在Ca2+与药物的比例达到0.5之前，变化最为显著。结合数据的分析表明，主要物种是一种2:1的药物:Ca2+“三明治”复合物，在25℃时估计解离常数为100 microM。一维核Overhauser效应（NOE）实验揭示了Ca2+结合前后药物中的空间连接性。这些变化与1H和13C化学位移的变化表明，在存在Ca2+的情况下，吡啶部分的4 - 芳基环取代基向C3 - 侧链移动得更近。这种吸引力是通过芳基间位NO2中的氧原子和二氢吡啶环侧链中的COOCH2基团对Ca2+离子的螯合作用实现的，并产生了稳定的顺式平面构象。从获得的相当有限的NOE数据推断，在乙腈中硝苯地平的Ca2+复合物中也观察到了对这种构象的偏好。我们的研究为尼卡地平提供了详细的溶液结构，也为Ca2+在该药物以及可能其他二氢吡啶类药物作用中的作用提出了建议。
