Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo
Acyclic Cucurbit[n]uril-Type Molecular Containers Bind Neuromuscular Blocking Agents In Vitro and Reverse Neuromuscular Block In Vivo
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DOI：
10.1002/anie.201206031
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Isaacs, Lyle
中科院分区：
文献类型：
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作者：
Ma, Da;Zhang, Ben;Isaacs, Lyle
每年，超过 4 亿名患者在手术室、重症监护室和急诊科的麻醉期间接受箭毒型神经肌肉阻滞剂 (NMBA)。临床麻醉中广泛使用的NMBA包括罗库溴铵、泮库溴铵、维库溴铵、阿曲库铵和顺式阿曲库铵。 [1]为了加速患者肌肉功能的恢复并防止残留的神经肌肉阻滞，往往需要在手术结束时逆转NMBA的生物学效应。 [2]传统的逆转剂，如新斯的明和依酚铵，通过竞争性抑制乙酰胆碱酯酶来增加神经肌肉接头处的乙酰胆碱水平，从而发挥其活性。 [3]不幸的是，这些传统的逆转剂可能会由于其对毒蕈碱乙酰胆碱受体的非选择性增强而引起心血管副作用，并且在临床实践中，当在没有 NMBA 的情况下使用时，甚至可能诱导（去极化）神经肌肉阻滞。 [4]临床麻醉领域的一项重大进展是引入了一种名为 Sugammadex 的 g-环糊精衍生分子容器（3，由默克公司以 Bridion 名义销售，2010 年销售额超过 1 亿美元；方案 1），它在水中以高亲和力 (Ka= 1.05 × 107 mÀ1) 结合罗库溴铵，并逆转罗库溴铵和维库溴铵在体内的作用。 [5] Sugammadex 通过将罗库溴铵和维库溴铵隔离在血液中来逆转神经肌肉阻滞，从而减少它们在神经肌肉接头处的浓度。 [6]舒更葡糖·罗库溴铵复合物随后通过尿液排出。 Sugammadex 对欧洲的麻醉临床实践产生了重大影响，但由于潜在的过敏反应和出血副作用，尚未批准在美国使用。 [7]因此，确实需要开发替代类别的分子容器，作为所有临床上重要的 NMBA 的逆转剂。我们和其他人一直在研究称为葫芦 [n] 脲 (CB [n]) 的新分子容器家族的合成和超分子化学，该分子容器由由 2n CH2 桥连接的 n 个甘脲环组成。 [8] CB [n] 分子容器的定义结构特征是由两个对称等效静电负脲基 C= O 门户保护的疏水空腔。值得注意的是，CB [n] 化合物对水中的烷（二）铵离子表现出异常高的亲和力（Ka 通常超过 109 m±1）。 [9]因此，CB [n] 化合物已用于多种应用，包括刺激响应分子机器、传感整体、仿生过程、超分子聚合物和（靶向）药物输送。 [10]考虑到 CB [n]· 客体通常观察到的高 Ka 值
Annually, more than 400 million patients receive curare-type neuromuscular blocking agents (NMBAs) during anesthesia in operating rooms, intensive care units, and emergency medicine departments. NMBAs that are widely used in the clinical practice of anesthesia include rocuronium, pancuronium, vecuronium, atracurium, and cisatracurium.[1] To speed up the recovery of the patient s muscle function and to prevent residual neuromuscular block, it is often necessary to reverse the biological effect of NMBAs at the end of the surgery.[2] Conventional reversal agents, such as neostigmine and edrophonium, exert their activity by increasing the levels of acetylcholine at the neuromuscular junction by competitive inhibition of acetylcholine esterase.[3] Unfortunately, these conventional reversal agents may cause cardiovascular side effects owing to their nonselective potentiation of muscarinic acetylcholine receptors and may even induce a (depolarizing) neuromuscular block in clinical practice when given in the absence of a NMBA.[4] A major advance in clinical anesthesia was made by the introduction of a g-cyclodextrin-derived molecular container known as Sugammadex (3, marketed as Bridion by Merck with sales of more than $100 million in 2010; Scheme 1), which binds rocuronium with high affinity (Ka= 1.05 107 mÀ1) in water and reverses the effects of rocuronium and vecuronium in vivo.[5] Sugammadex reverses neuromuscular block by sequestering rocuronium and vecuronium in the bloodstream, thereby depleting their concentration at the neuromuscular junction.[6] The sugammadex· rocuronium complexes are subsequently excreted in the urine. Sugammadex has had a major impact on the clinical practice of anesthesia in Europe but is not yet approved for use in the United States because of potential allergic reactions and hemorrhagic side effects.[7] As a result, there is a real need to develop alternative classes of molecular containers that function as reversal agents for the full range of clinically important NMBAs.We, and others, have been studying the synthesis and supramolecular chemistry of a new family of molecular containers known as cucurbit [n] urils (CB [n]), which comprise n glycoluril rings linked by 2n CH2 bridges.[8] The defining structural features of CB [n] molecular containers are a hydrophobic cavity guarded by two symmetry-equivalent electrostatically negative ureidyl C= O portals. Remarkably, CB [n] compounds display unusually high affinity (Ka routinely exceeds 109 mÀ1) toward alkane (di) ammonium ions in water.[9] Accordingly, CB [n] compounds have been used in a variety of applications including stimuli-responsive molecular machines, sensing ensembles, biomimetic processes, supramolecular polymers, and (targeted) drug delivery.[10] Given the high Ka values typically observed for CB [n]· guest