主客体络合驱动的开环葫芦脲对琥珀胆碱神经肌肉阻滞的快速拮抗

doi:10.6023/cjoc202601042

摘要/Abstract

设计合成了7个新的开环葫芦脲化合物, 用于研究其通过主客体结合拮抗琥珀胆碱肌肉松弛活性的功能. 研究发现, 化合物ACB-p2具有高水溶性和生物相容性, 对小鼠的最大耐受剂量高达1500 mg/kg. 化合物ACB-p2对临床唯一的短效神经肌肉阻滞剂琥珀胆碱(SCH)具有高结合亲和力(结合常数K_a=1.7×10⁵ L•mol^－1). ¹H NMR实验和密度泛函理论计算研究表明, ACB-p2主要通过其疏水空腔包结琥珀胆碱的胆碱片段实现高效结合, 并进一步通过多重分子间 C—H…O氢键作用稳定. 大鼠试验模型揭示, 80和160 mg/kg剂量的ACB-p2可快速拮抗琥珀胆碱引发的神经肌肉阻滞作用, 能将大鼠自主呼吸恢复时间从平均195 s显著缩短至38和23 s, 分别对应于11.8和5.9倍的治疗指数, 显示出开环葫芦脲快速拮抗琥珀胆碱的潜力.

关键词: 主客体化学, 开环葫芦脲, 琥珀胆碱, 解药, 神经肌肉阻滞, 超分子拮抗, 药物设计

Seven new acyclic cucurbit[n]urils have been prepared. Compound ACB-p2 displays high water-solubility and high biocompatibility, with maximum tolerated dose reaching 1500 mg/kg for mice. The compound is revealed to have high binding affinity (K_a=1.7×10⁵ L•mol^－1) in water for succinylcholine (SCH), clinically used short-duration neuromuscular blocking agent. ¹H NMR and density functional theory calculation show that ACB-p2 binds to SCH mainly by encapsulating the choline segment of SCH in its hydrophobic cavity, which is stabilized by multiple intermolecular C—H…O hydrogen bonds. The high binding affinity of ACB-p2 for SCH leads to rapid antagonism of the neuromuscular blockade of SCH. For rats, compound ACB-p2 of the 80 and 160 mg/kg doses is capable of shortening the recovery time for spontaneous respiration averagely from 195 s to 38 and 23 s, respectively, corresponding to therapeutic an index of 11.8 and 5.9.

Key words: host-guest chemistry, acyclic cucurbit[n]uril, succinylcholine, antidote, neuromuscular blockade, supramolecular antagonism, drug design

引用此文

张丹维, 高睿, 冯科, 余尚博, 王辉, 周伟, 黎占亭. 主客体络合驱动的开环葫芦脲对琥珀胆碱神经肌肉阻滞的快速拮抗[J]. 有机化学, 2026, 46(9): 3722-3730.

Dan-Wei Zhang, Rui Gao, Ke Feng, Shangbo Yu, Hui Wang, Wei Zhou, Zhan-Ting Li. Acyclic Cucurbit[n]uril as Supramolecular Antagonist for Rapidly Reversing the Neuromuscular Blockade of Succinylcholine through Host-Guest Complexation[J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3722-3730.

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图/表 7

Scheme 1. Chemical structures of acyclic cucurbit[n]urils ACB-p1~ACB-p7, succinylcholine (SCH), decamethonium bromide (DCM), and mivacurium (MIV)

Scheme 2. Synthetic routes for compounds ACB-p1~ACB-p7

	Solubility/ (mg•mL^－1)	K_a^b/(×10³ L•mol^－1)
	Solubility/ (mg•mL^－1)	SCH	DCM	MIV
ACB-p1 ACB-p2 ACB-p3 ACB-p4 ACB-p5 ACB-p6 ACB-p7	65 225 62 75 78 124 216	230±9.1 150±7.7 12±0.98 1.0±0.099 130±5.1 67±2.6 79±12	210±8.7 170±6.6 —^c —^c 160±6.1 139±8.2 170±7.9	1.7±0.71 15±0.95 9.1±1.4 7.2±1.7 8.9±0.57 2.9±0.60 8.3±0.22

Table 1. Summary of water-solubility of ACB-p1~ACB-p7 and the binding constants (Ka) of their complexes with blocking agentsa

Figure 1. (a) ITC profile recorded by adding ACB-p2 (3.0 mmol/L) into the solution of SCH (0.3 mmol/L) in water (The solid line represents the best non-linear fit of the data to a 1∶1 binding model); (b) Chemical shift changes of H-a~H-d signals (Scheme 1) of SCH (1.0 mmol/L) with the addition of increasing amount of ACB-p2 (0~2.0 mmol/L) in 1H NMR spectra in D2O

Figure 2. DFT-optimized minimal-energy structures of complex ACB-p2·SCH, highlighting multiple intermolecular (SCH) C—H…O (carboxylate of ACB-p2) hydrogen bonds

Figure 3. (a) Viability of Hek293 cell lines treated with ACB-p2 of increasing concentration (0~256.0 μg/mL); (b) Relative body weight changes of mice versus the observation day after intravenous injection of ACB-p2 of different doses and saline; (c) H & E staining images of the tissues of the major organs (heart, liver, spleen, lung and kidney) collected from rats of the group treated with ACB-p2 of 1.5 g/kg dose and the saline group on the last observation day

Figure 4. Recovery time of rats (n=6, 3 female＋3 male) for spontaneous respiration from SCH-induced neuromuscular blockade by ACB-p2 The dose of SCH was 0.8 mg/kg. Intravenous injection of saline and ACB-p2 was given at T1=0.1. The recovery time was defined by the period from injection to TOF → 90%

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