Ntountaniotis Dimitrios, Kellici Tahsin, Tzakos Andreas, Kolokotroni Pinelopi, Tselios Theodore, Becker-Baldus Johanna, Glaubitz Clemens, Lin Sonyan, Makriyannis Alexandros, Mavromoustakos Thomas
National and Kapodistrian University of Athens, Department of Chemistry, Panepistimioupolis Zografou 15771, Athens, Greece.
National and Kapodistrian University of Athens, Department of Chemistry, Panepistimioupolis Zografou 15771, Athens, Greece; University of Ioannina, Department of Chemistry, 45110 Ioannina, Greece.
Biochim Biophys Acta. 2014 Oct;1838(10):2439-50. doi: 10.1016/j.bbamem.2014.06.003. Epub 2014 Jun 16.
ΑΤ1 receptor (AT1R) antagonists exert their antihypertensive effects by preventing the vasoconstrictive hormone AngII to bind to the AT1 receptor. It has been proposed that these biological effects are mediated through a two-step mechanism reaction. In the first step, they are incorporated in the core of the lipid bilayers and in the second step they reach the active site of the receptor through lateral diffusion. In this model, drug/membrane interactions are key elements for the drugs achieving inhibition at the AT1 receptor. In this work, the interactions of the prodrug candesartan cilexetil (TCV-116) with lipid bilayers are studied at molecular detail. Solid-state (13)C-CP/MAS, 2D (1)H-(1)H NOESY NMR spectroscopy and in silico calculations are used. TCV-116 and olmesartan, another drug which acts as an AT1R antagonist are compared for their dynamic effects in lipid bilayers using solid-state (2)H-NMR. We find a similar localization of TCV-116 compared to other AT1 antagonists in the intermediate polar region. In addition, we can identify specific local interactions. These interactions may be associated in part with the discrete pharmacological profiles observed for different antagonists.
血管紧张素Ⅱ 1型受体（AT1R）拮抗剂通过阻止血管收缩激素血管紧张素Ⅱ（AngII）与AT1受体结合来发挥其降压作用。有人提出，这些生物学效应是通过两步机制反应介导的。第一步，它们融入脂质双层的核心，第二步，它们通过横向扩散到达受体的活性位点。在这个模型中，药物/膜相互作用是药物在AT1受体上实现抑制作用的关键因素。在这项工作中，对前药坎地沙坦酯（TCV-116）与脂质双层的相互作用进行了分子层面的详细研究。使用了固态（13）C-CP/MAS、二维（1）H-（1）H NOESY核磁共振光谱以及计算机模拟计算。使用固态（2）H-NMR比较了TCV-116和另一种作为AT1R拮抗剂的药物奥美沙坦在脂质双层中的动态效应。我们发现，与其他AT1拮抗剂相比，TCV-116在中间极性区域的定位相似。此外，我们可以识别特定的局部相互作用。这些相互作用可能部分与不同拮抗剂观察到的离散药理学特征有关。
