Abstract Local anesthetics promote analgesia by interacting with excitable membranes. Articaine (ATC) has a unique composition among local anesthetics as it possesses a thiophene instead of the typical phenyl ring. Aiming to characterize the interaction of neutral articaine (nATC) with phospholipid membranes, we have employed a synergistic approach of experimental and computational techniques. Fluorescence measurements supported nATC partitioning into the membranes, since its intrinsic fluorescence anisotropy increased from 0.03 in water to 0.29 in the presence of egg phosphatidylcholine (EPC) liposomes, and the fluorescence of AHBA, a probe that monitors the water-membrane interface, was quenched by nATC. 1H NMR experiments revealed changes in the chemical shifts of articaine and EPC hydrogens after partitioning, and shorter T1 values of nATC hydrogens when inserted into the EPC vesicles. Contacts of nATC and the phospholipid polar head group were inferred from 2D-NOE. Taken together, these results indicate a superficial insertion of the nATC molecules inside EPC bilayers. This conclusion was confirmed by molecular dynamics simulations, which allowed the identification of the key interactions underlying the preferential location of nATC in the bilayer. Contrary to what is often stated (that articaine is a high lipophilic local anesthetic agent) our results place ATC among the hydrophilic ones, such as lidocaine, prilocaine, and mepivacaine, for which the water/membrane interface is the preferred location.

中文翻译：

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Articaine 与磷脂双分子层的相互作用

摘要 局部麻醉剂通过与可兴奋膜相互作用来促进镇痛。Articaine (ATC) 在局部麻醉剂中具有独特的成分，因为它具有噻吩而不是典型的苯环。为了表征中性阿替卡因 (nATC) 与磷脂膜的相互作用，我们采用了实验和计算技术的协同方法。荧光测量支持 nATC 分配到膜中，因为其固有荧光各向异性从水中的 0.03 增加到在卵磷脂 (EPC) 脂质体存在下的 0.29，并且 AHBA（一种监测水膜界面的探针）的荧光被淬灭通过 nATC。1H NMR 实验揭示了分配后阿替卡因和 EPC 氢的化学位移的变化，当插入 EPC 囊泡时，nATC 氢的 T1 值更短。从 2D-NOE 推断 nATC 和磷脂极性头基的接触。总之，这些结果表明 nATC 分子在 EPC 双层内的表面插入。这一结论得到了分子动力学模拟的证实，它允许识别双层中 nATC 优先位置的关键相互作用。与通常所说的（阿替卡因是一种高亲脂性局部麻醉剂）相反，我们的结果将 ATC 置于亲水性麻醉剂中，例如利多卡因、丙胺卡因和甲哌卡因，其中水/膜界面是首选位置。这些结果表明 nATC 分子在 EPC 双层内的表面插入。这一结论得到了分子动力学模拟的证实，它允许识别双层中 nATC 优先位置的关键相互作用。与通常所说的（阿替卡因是一种高亲脂性局部麻醉剂）相反，我们的结果将 ATC 置于亲水性麻醉剂中，例如利多卡因、丙胺卡因和甲哌卡因，其中水/膜界面是首选位置。这些结果表明 nATC 分子在 EPC 双层内的表面插入。这一结论得到了分子动力学模拟的证实，它允许识别双层中 nATC 优先位置的关键相互作用。与通常所说的（阿替卡因是一种高亲脂性局部麻醉剂）相反，我们的结果将 ATC 置于亲水性麻醉剂中，例如利多卡因、丙胺卡因和甲哌卡因，其中水/膜界面是首选位置。