A novel oxime platform, the substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937), was invented at Mississippi State University with an objective of discovering a brain-penetrating antidote to highly potent organophosphate anticholinesterases, such as the nerve agents. The goal was reactivation of inhibited brain acetylcholinesterase to attenuate the organophosphate-induced hypercholinergic activity that results in glutamate-mediated excitotoxicity and neuropathology. The currently approved oxime antidote in the US, 2-PAM, cannot do this. Using highly relevant surrogates of sarin and VX that leave acetylcholinesterase phosphylated with the same chemical moiety as their respective nerve agents, in vitro screens and in vivo tests in rats were conducted to identify the most efficacious members of this platform. The most promising novel oximes provided 24-h survival of lethal level surrogate exposure better than 2-PAM in almost all cases, and two of the oximes shortened the time to cessation of seizure-like behavior while 2-PAM did not. The most promising novel oximes attenuated neuropathology as indicated by immunohistochemical stains for both glia and neurons, while 2-PAM did not protect either glia or neurons. These results strongly suggest that these novel oximes can function within the brain to protect it, and therefore show great promise as potential future nerve agent antidotes.

中文翻译：

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沙林和VX的替代品抑制乙酰胆碱酯酶的新型中枢活性肟活化剂。

密西西比州立大学发明了一种新的肟平台，即取代的苯氧基烷基吡啶鎓肟（美国专利9,227,937），目的是发现一种穿透脑的解毒剂，以治疗强效的有机磷酸酯抗胆碱酯酶，例如神经毒剂。目的是重新激活受抑制的脑乙酰胆碱酯酶，以减弱有机磷酸酯诱导的高胆碱能活性，从而导致谷氨酸介导的兴奋性毒性和神经病理学。美国目前批准的肟解毒剂2-PAM无法做到这一点。使用高度相关的沙林蛋白和VX替代物，使乙酰胆碱酯酶被与各自神经毒物相同的化学部分磷酸化，在大鼠中进行了体外筛选和体内试验，以鉴定该平台中最有效的成员。在几乎所有情况下，最有希望的新型肟都能提供比2-PAM更好的致死水平替代物暴露24小时存活率，其中两种肟缩短了停止癫痫样行为的时间，而2-PAM则没有。如神经胶质和神经元的免疫组织化学染色所示，最有希望的新型肟减弱了神经病理学，而2-PAM既不保护神经胶质也不保护神经元。这些结果强烈表明，这些新型肟可以在大脑中发挥功能来保护大脑，因此作为潜在的未来神经毒剂解毒剂具有广阔的前景。如神经胶质和神经元的免疫组织化学染色所示，最有希望的新型肟减弱了神经病理学，而2-PAM既不保护神经胶质也不保护神经元。这些结果强烈表明，这些新型肟可以在大脑中发挥功能来保护大脑，因此作为潜在的未来神经毒剂解毒剂具有广阔的前景。如神经胶质和神经元的免疫组织化学染色所示，最有希望的新型肟减弱了神经病理学，而2-PAM既不保护神经胶质也不保护神经元。这些结果强烈表明，这些新型肟可以在大脑中发挥功能来保护大脑，因此作为潜在的未来神经毒剂解毒剂具有广阔的前景。