Amidine-Oximes: Reactivators for Organophosphate Exposure
Amidine-Oximes: Reactivators for Organophosphate Exposure
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DOI：
10.1021/jm200054r
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发表时间：
2011-05-12
影响因子：
7.3
通讯作者：
Cashman, John R.
中科院分区：
文献类型：
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作者：
Kalisiak, Jaroslaw;Ralph, Erik C.;Cashman, John R.
设计、合成并测试了一类新型有机磷酸酯 (OP) 抑制胆碱酯酶 (ChE) 的脒肟再激活剂。这些化合物代表了一组新型肟，具有增强的穿过血脑屏障的能力。缺乏脑部渗透性是目前使用肟作为OP中毒解毒剂的主要限制。本文描述的概念依赖于脒残基和肟官能团的组合，由此脒增加对ChE的结合亲和力，并且肟负责重新激活。脒肟经过体外测试，OP-BuChE 的再激活率高于解磷定 (2-PAM) 或单异亚硝基丙酮 (MINA)。 OP-AChE 的脒肟再激活率低于 2-PAM，但高于 MINA。用肟15c和15d（145μmol/kg，腹腔注射）预处理30分钟后，用梭曼模型化合物攻击小鼠。另外，在后处理实验中测试了15天（145μmol/kg，腹腔注射，沙林模型化合物暴露后5分钟给药）。在这两种情况下，脒肟在 OP 暴露的动物模型中都能提供 100% 的 24 小时存活率。
A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of oximes with enhanced capabilities of crossing the blood-brain barrier. Lack of brain penetration is a major limitation for currently used oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and oxime functionality whereby the amidine increases the binding affinity to the ChE and the oxime is responsible for reactivation. Amidine-oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidoxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine-oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with oximes 15c and 15d (145 mu mol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 mu mol/kg, ip, administration 5 min after sarin model compound exposure). In both cases, amidine-oximes afforded 100% 24 h survival in an animal model of OP exposure.