Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, Munich 80937, Germany; Walther-Straub-Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Goethestr. 33, Munich 80336, Germany.
Chemical, Biological and Radiological (CBR) Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Toxicol Lett. 2024 Jun;397:42-47. doi: 10.1016/j.toxlet.2024.04.015. Epub 2024 May 7.
Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2'-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR.
有机磷农药中毒对全球的医疗体系构成挑战。此外，神经毒剂仍然是持续存在的威胁。几十年来，有机磷中毒的治疗方法几乎没有改变，主要依赖于对症治疗和使用肟类药物间接恢复神经肌肉功能。因此，直接针对烟碱型乙酰胆碱受体（nAChR）的化合物可能会极大地改善治疗选择。本研究在大鼠膈神经模型中使用间接场刺激，研究了一系列具有三甲撑或 2,2'-二乙氧基连接基团的双吡啶鎓类似物。在刺激频率为 20 Hz 时，甲基和乙基取代的双吡啶鎓类似物将神经肌肉功能恢复至 37 ± 17%（MB419，一种 3-甲基类似物）。具有 2-或 3-甲基或 2-或 3-乙基取代基的双吡啶鎓类似物比具有 4-甲基或 4-乙基取代基的类似物更倾向于恢复更高水平的神经肌肉功能。目前的数据可用于未来的研究，以优化针对 nAChR 的化合物的基于结构的分子建模。
