Turner Simon R, Timperley Christopher M, Bird Mike, Green A Christopher, Price Matthew E, Rice Helen, Chad John E, Tattersall John E H
Chemical, Biological and Radiological Sciences Division, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire, United Kingdom.
School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
PLoS One. 2025 Feb 25;20(2):e0318508. doi: 10.1371/journal.pone.0318508. eCollection 2025.
The standard treatment of atropine and oximes is insufficiently effective against all organophosphorus nerve agents. Bispyridinium non-oxime nicotinic antagonists are promising components to add to treatments. One of these, MB327, improves the survival of guinea-pigs after intoxication with tabun, sarin or soman. We extend our previous study of unsubstituted bispyridinium non-oximes with C1 to C10 alkane linkers to analogues having 4-tert-butylpyridinium rings and the same linker range. We report their effects on nicotinic-mediated calcium responses in muscle-derived (CN21) cells where nicotinic responses were inhibited in a concentration-dependent manner. A clear structure-activity relationship resulted: the inhibitory potency increased as the linker lengthened. Previous data showed the inhibition of human acetylcholinesterase in vitro increased similarly and that in general the toxicity to mice increased accordingly. However, the shorter analogues MB327 (4-tert-butyl C3) and MB442 (unsubstituted C5) compared favourably in toxicity to some oximes used to treat nerve agent poisoning. Like MB327, the non-oxime MB442, selected by the process described, improved the survival of guinea-pigs intoxicated with soman when combined with hyoscine and physostigmine or atropine and avizafone. Our research has now afforded two compounds able to protect guinea-pigs against nerve agent toxicity through a mechanism not previously exploited deliberately for this purpose.
阿托品和肟类药物的标准治疗方法对所有有机磷神经毒剂的疗效都不够理想。双吡啶鎓非肟类烟碱拮抗剂有望成为治疗方案中的有效成分。其中一种化合物MB327，可提高豚鼠在被塔崩、沙林或梭曼中毒后的存活率。我们将之前对带有C1至C10烷烃连接基的未取代双吡啶鎓非肟类化合物的研究扩展到了具有4-叔丁基吡啶鎓环且连接基范围相同的类似物。我们报告了它们对肌肉来源的（CN21）细胞中烟碱介导的钙反应的影响，在这些细胞中烟碱反应呈浓度依赖性受到抑制。由此得出了明确的构效关系：随着连接基变长，抑制效力增强。先前的数据表明，体外对人乙酰胆碱酯酶的抑制作用也有类似增加，总体而言对小鼠的毒性也相应增加。然而，较短的类似物MB327（4-叔丁基C3）和MB442（未取代C5）在对一些用于治疗神经毒剂中毒的肟类药物的毒性方面表现更优。与MB327一样，通过上述方法筛选出的非肟类化合物MB442，与东莨菪碱和毒扁豆碱或阿托品和阿维扎封联合使用时，可提高被梭曼中毒的豚鼠的存活率。我们的研究现已获得两种化合物，它们能够通过一种此前未被特意用于此目的的机制保护豚鼠免受神经毒剂的毒性侵害。
