PDF(Pubmed)
Abstract：
The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP-inhibited acetylcholinesterase (AChE) which can penetrate the blood-brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24-h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP-inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%-102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2-PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy.
摘要：
目前，有机磷（OP）抗胆碱酯酶的治疗缺乏有效的OP抑制乙酰胆碱酯酶（AChE）的肟再激活剂，该激活剂可以穿透血脑屏障（BBB）。我们的实验室已经合成了新型的取代的苯氧基烷基吡啶肟，并测试了它们促进被致死剂量的神经毒剂替代物攻击的大鼠存活的能力。这些先前的研究证明了这些肟中的一些能够促进对沙林和VX的高度相关替代品的致死水平的大鼠的24小时存活。外周组织中OP抑制的AChE的再激活可能是它们在致死OP攻击的存活中的功效的主要促成因素。在本研究中,使用两种神经毒剂替代品：邻苯二甲酰亚胺基异丙基甲基膦酸酯（PIMP，沙林代用品)和甲基膦酸4-硝基苯基乙酯(NEMP，VX代理)。在两种组织类型中,肟在体外表现出23%-102%的AChE再活化范围。在本研究中测试的一些新型肟证明了比目前批准的肟更有效地重新激活血清中的AChE的能力，2-PAM.因此,这些新型肟中的一些具有逆转外周靶组织中的AChE抑制的潜力,并有助于存活功效。
