Partitioning and location of Bay K 8644, 1,4-dihydropyridine calcium channel agonist, in model and biological membranes.
Partitioning and location of Bay K 8644, 1,4-dihydropyridine calcium channel agonist, in model and biological membranes.
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Bay K 8644（1,4-二氢吡啶钙通道激动剂）在模型和生物膜中的划分和位置。
DOI：
10.1016/s0006-3495(89)82875-9
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发表时间：
1989
影响因子：
3.4
通讯作者：
Herbette,LG
中科院分区：
文献类型：
--
作者：
Mason,RP;Gonye,GE;Chester,DW;Herbette,LG
一些证据表明，非特异性药物与脂质双分子层的相互作用在随后的识别和结合膜中的特异性受体位点中起着重要作用。采用小角X-射线衍射技术，在分子水平上研究了Bay K 8644（一种1，4-二氢吡啶（DHP）钙通道激动剂）与模型和生物膜的相互作用。通过放射化学分析检查进入膜的非特异性药物分配。测定了[3 H] Bay K 8644在二棕榈酰磷脂酰胆碱（DPPC）囊泡（高于和低于其热相变温度（Tm））和兔骨骼肌轻肌浆网（LSR）中的非特异性结合特性。在DPPC中，分配系数Kp高于Tm（55 ℃）14，000，而在凝胶相中（2 ℃）为160。在LSR膜中测定的Kp为10，700。DPPC和LSR膜的这些值可以与传统辛醇/缓冲液系统中的Kp=290进行比较。使用小角度X-射线衍射，电子致密的三氟甲基基团的海湾K 8644在DPPC（高于Tm）和纯化的心脏肌膜（CSL）脂质双层的平衡位置被确定为始终位于这些膜的脂肪酰基链的前几个亚甲基片段的区域内。该位置与DHP钙通道拮抗剂尼莫地平和Bay P 8857观察到的位置相似。我们认为，这个特定的膜位置定义了一个区域的局部药物浓度和平面的横向扩散到一个共同的受体网站。在DPPC膜Tm下方，Bay K 8644被排除在这个能量有利的位置之外，进入双层间水空间。将DPPC双层加热到Tm（55 ℃）以上表明这种排斥是可逆的，并表明药物-膜相互作用取决于双层的物理状态。在这些系统中的任何特定的蛋白结合位点的情况下，使我们能够确定潜在的重要作用，散装脂质相可能发挥的分子机制DHP结合到与钙通道相关的特定受体位点。
Several lines of evidence suggest that nonspecific drug interaction with the lipid bilayer plays an important role in subsequent recognition and binding to specific receptor sites in the membrane. The interaction of Bay K 8644, a 1,4-dihydropyridine (DHP) calcium channel agonist, with model and biological membranes was examined at the molecular level using small angle x-ray diffraction. Nonspecific drug partitioning into the membrane was examined by radiochemical assay. Nonspecific binding characteristics of [3H] Bay K 8644 were determined in both dipalmitoyl phosphatidylcholine (DPPC) vesicles above and below their thermal phase transition (Tm) and rabbit skeletal muscle light sarcoplasmic reticulum (LSR). In DPPC, the partition coefficient, Kp, was 14,000 above the Tm (55 degrees C) versus 160 in the gel phase (2 degrees C). The Kp determined in LSR membranes was 10,700. These values for both DPPC and LSR membranes can be compared with Kp=290 in the traditional octanol/buffer system. Using small-angle x-ray diffraction, the equilibrium position of the electron-dense trifluoromethyl group of Bay K 8644 in DPPC (above Tm) and purified cardiac sarcolemmal (CSL) lipid bilayers was determined to be consistently located within the region of the first few methylene segments of the fatty acyl chains of these membranes. This position is similar to that observed for the DHP calcium channel antagonists nimodipine and Bay P 8857. We suggest this particular membrane location defines a region of local drug concentration and plane for lateral diffusion to a common receptor site. Below the DPPC membrane Tm, Bay K 8644 was shown to be excluded from this energetically favored position into the interbilayer water space. Heating the DPPC bilayer above the Tm (55 degrees C) showed that this exclusion was reversible and indicates that drug-membrane interaction is dependent on the bilayer physical state. The absence of any specific protein binding sites in these systems allows us to ascertain the potentially important role that the bulk lipid phase may play in the molecular mechanism of DHP binding to the specific receptor site associated with the calcium channel.