Ntountaniotis Dimitrios, Mali Gregor, Grdadolnik Simona Golic, Halabalaki Maria, Skaltsounis Alexios-Leandros, Potamitis Constantinos, Siapi Eleni, Chatzigeorgiou Petros, Rappolt Michael, Mavromoustakos Thomas
Department of Chemistry, University of Patras, Patras 26500, Greece.
Biochim Biophys Acta. 2011 Dec;1808(12):2995-3006. doi: 10.1016/j.bbamem.2011.08.001. Epub 2011 Aug 6.
It is proposed that AT1 antagonists (ARBs) exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT1 receptor. Thus, lipid bilayers are expected to be actively involved and play a critical role in drug action. For this reason, the thermal, dynamic and structural effects of olmesartan alone and together with cholesterol were studied using differential scanning calorimetry (DSC), 13C magic-angle spinning (MAS) nuclear magnetic resonance (NMR), cross-polarization (CP) MAS NMR, and Raman spectroscopy as well as small- and wide angle X-ray scattering (SAXS and WAXS) on dipalmitoyl-phosphatidylcholine (DPPC) multilamellar vesicles. 13C CP/MAS spectra provided direct evidence for the incorporation of olmesartan and cholesterol in lipid bilayers. Raman and X-ray data revealed how both molecules modify the bilayer's properties. Olmesartan locates itself at the head-group region and upper segment of the lipid bilayers as 13C CP/MAS spectra show that its presence causes significant chemical shift changes mainly in the A ring of the steroidal part of cholesterol. The influence of olmesartan on DPPC/cholesterol bilayers is less pronounced. Although, olmesartan and cholesterol are residing at the same region of the lipid bilayers, due to their different sizes, display distinct impacts on the bilayer's properties. Cholesterol broadens significantly the main transition, abolishes the pre-transition, and decreases the membrane fluidity above the main transition. Olmesartan is the only so far studied ARB that increases the gauche:trans ratio in the liquid crystalline phase. These significant differences of olmesartan may in part explain its distinct pharmacological profile.
有人提出，血管紧张素Ⅱ1型受体拮抗剂（ARBs）通过插入脂质膜并扩散至血管紧张素Ⅱ1型受体的活性位点来发挥其生物学作用。因此，预计脂质双层会积极参与并在药物作用中发挥关键作用。出于这个原因，使用差示扫描量热法（DSC）、13C魔角旋转（MAS）核磁共振（NMR）、交叉极化（CP）MAS NMR、拉曼光谱以及小角和广角X射线散射（SAXS和WAXS），研究了奥美沙坦单独以及与胆固醇一起对二棕榈酰磷脂酰胆碱（DPPC）多层囊泡的热、动力学和结构影响。13C CP/MAS光谱为奥美沙坦和胆固醇掺入脂质双层提供了直接证据。拉曼和X射线数据揭示了这两种分子如何改变双层的性质。如13C CP/MAS光谱所示，奥美沙坦位于脂质双层的头部区域和上部，其存在主要导致胆固醇甾体部分A环的显著化学位移变化。奥美沙坦对DPPC/胆固醇双层的影响不太明显。虽然奥美沙坦和胆固醇位于脂质双层的同一区域，但由于它们大小不同，对双层性质的影响也不同。胆固醇显著拓宽了主要转变，消除了预转变，并降低了主要转变以上的膜流动性。奥美沙坦是迄今为止研究的唯一一种能增加液晶相中gauche:trans比例的ARB。奥美沙坦的这些显著差异可能部分解释了其独特的药理学特征。
