Organophosphorus nerve agents (NAs) are the most lethal chemical warfare agents and have been used by state and non-state actors since their discovery in the 1930s. They covalently modify acetylcholinesterase, preventing the breakdown of acetylcholine (ACh) with subsequent loss of synaptic transmission, which can result in death. Despite the availability of several antidotes for OPNA exposure, none directly targets the nicotinic acetylcholine receptor (nAChR) mediated component of toxicity. Non-oxime bispyridinium compounds (BPDs) have been shown previously to partially counteract the effects of NAs at skeletal muscle tissue, and this has been attributed to inhibition of the muscle nAChR. Functional data indicate that, by increasing the length of the alkyl linker between the pyridinium moieties of BPDs, the antagonistic activity at nAChRs can be improved. Molecular dynamics simulations of the adult muscle nAChR in the presence of BPDs identified key residues likely to be involved in binding. Subsequent two-electrode voltage clamp recordings showed that one of the residues, εY131, acts as an allosteric determinant of BPD binding, and that longer BPDs have a greater stabilizing effect on the orthosteric loop C than shorter ones. The work reported will inform future design work on novel antidotes for treating NA exposure.

中文翻译：

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非肟双吡啶神经毒剂解毒剂化合物与成人肌肉 nAChR 结合的分子决定因素

有机磷神经毒剂 (NAs) 是最致命的化学战剂，自 1930 年代被发现以来一直被国家和非国家行为者使用。它们共价修饰乙酰胆碱酯酶，防止乙酰胆碱 (ACh) 分解，随后失去突触传递，从而导致死亡。尽管有几种针对 OPNA 暴露的解毒剂，但没有一种直接针对烟碱乙酰胆碱受体 (nAChR) 介导的毒性成分。先前已显示非肟双吡啶鎓化合物 (BPD) 可部分抵消 NA 在骨骼肌组织中的作用，这归因于对肌肉 nAChR 的抑制。功能数据表明，通过增加 BPD 的吡啶鎓部分之间的烷基接头长度，可以提高对 nAChRs 的拮抗活性。在存在 BPD 的情况下，成人肌肉 nAChR 的分子动力学模拟确定了可能参与结合的关键残基。随后的双电极电压钳记录显示，其中一个残基，ε131，作为 BPD 结合的变构决定因素，并且较长的 BPD 对正构环 C 的稳定作用比较短的 BPD 更大。报告的工作将为未来治疗 NA 暴露的新型解毒剂的设计工作提供信息。并且较长的 BPD 对正构环 C 的稳定作用比较短的 BPD 更大。报告的工作将为未来治疗 NA 暴露的新型解毒剂的设计工作提供信息。并且较长的 BPD 对正构环 C 的稳定作用比较短的 BPD 更大。报告的工作将为未来治疗 NA 暴露的新型解毒剂的设计工作提供信息。