Study of a new antidote for nerve gas poisoning brought by chemical terrorism

化学恐怖主义神经毒气中毒新型解毒剂的研究

• 批准号: 16390518
• 负责人: TAKATRI Takehiko
• 金额: $ 3.97万
• 依托单位: National Research Institute of Police Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390518/
• 关键词: Sarin; 2-PAM; INMP; BBB; VX; Soman

To develop a new antidote that can be easily penetrate the blood-brain barrier (BBB) in organophosphate poisoning, twenty-three known and novel homologues of 2-, 3- and 4-PAM were synthesized. And, a non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was also synthesized for safe preparation of sarin-exposed acetylcholineesterase (AChE). Fifty percent inhibitory concentration (IC_50) of INMP on 0.01 U human erythrocytes, AChE was 15 nM. Then, the reactivation activities of synthesized PAM analogues to INMP-exposed human erythrocytes AChE were examined. 2-PAM itself showed the best recovery activity, and the activities of 2-PAM analogues were linearly reduced by elongation of the side chain. This could be explained as a result of the decrease of the dissociation constant (pKa) with the increase of lipophilicity of analogues or the increase in steric hindrance due to the side chain that may prevent the reaction of oxime group and inhibited AChE. All th … More e 3-PAM analogues showed low recovery activities in all chain length. In contrast, recovery activities of all the 4-PAM analogues were more than moderate and increased by side-chain elongation. Regarding the side chains of PAM analogues, linear hydrocarbons seemed to be more suitable than branched hydrocarbons seemed to be more suitable than branched hydrocarbons in terms of both activity and availability. On the other hand, all the alkylbenzyl analogues of 2-PAM and some alkylbenzyl analogues of 4-PAM tested showed strong reactivation activities. Next, the BBB penetration of 4-hydroxyiminomethyl-N-decyl pyridinium bromide, 4-hydroxyiminomethyl-N-octyl pyridinium bromide, 2-hydroxyiminomethyl -N-[p-(tert-butyl) benzyl] pyridinium bromide and 2-hydroxyiminomethyl-N-(p-benzyl) pyridinium bromide using a brain microdialysis technique was examined. However, it was not clear because of their strong heart toxicities. Furthermore, to perform the immunohistochemical assy, polyclonal antibodies specific to PAM analogues were produced using 4-hydroxyiminomethyl-N-(7-carboxyhepto-l-yl) pyridinium bromide coupled to Kehol Limpet Hemocyanin (KLH) with EDC/Diaminodipropylamine Immobilization Kit as an immunogen. Less

为了开发一种能有效穿透血脑屏障的新型有机磷中毒解毒剂，合成了23种2-、3-和4-PAM的已知和新同系物。此外，还合成了一种无毒、稳定的沙林类似物甲基膦酸对硝基苯异丙酯（INMP），用于安全制备沙林暴露的乙酰胆碱酯酶（AChE）。INMP对0.01 U人红细胞AChE的50%抑制浓度（IC_50）为15 nM。然后，合成的PAM类似物INMP暴露的人红细胞AChE的再活化活性进行了检查。2-PAM本身表现出最好的恢复活性，并且2-PAM类似物的活性随着侧链的延长而线性降低。这可能是由于类似物的亲脂性增加，离解常数（pKa）降低，或由于侧链的空间位阻增加，阻碍了肟基的反应，抑制了乙酰胆碱酯酶的活性。所有的 ...更多信息 e3-PAM类似物在所有链长下均表现出较低的回收活性。与此相反，所有的4-PAM类似物的恢复活动超过中等，增加侧链延长。关于PAM类似物的侧链，就活性和可用性而言，线性烃似乎比支链烃更合适。另一方面，所有的2-PAM的烷基苄基类似物和一些4-PAM的烷基苄基类似物显示出较强的再活化活性。接着，使用脑微透析技术检查4-羟基亚氨基甲基-N-癸基溴化吡啶、4-羟基亚氨基甲基-N-辛基溴化吡啶、2-羟基亚氨基甲基-N-[对-（叔丁基）苄基]溴化吡啶和2-羟基亚氨基甲基-N-（对-苄基）溴化吡啶的BBB渗透。然而，由于其强烈的心脏毒性，目前尚不清楚。此外，为了进行免疫组织化学分析，使用4-羟基亚氨基甲基-N-（7-羧基庚-1-基）溴化吡啶鎓与Kehol Limpet血蓝蛋白（KLH）偶联，用EDC/二氨基二丙胺固定试剂盒作为免疫原，产生对PAM类似物特异性的多克隆抗体。少

项目成果

Sarin poisonong diagnosis in the Tokyo subway.

东京地铁沙林中毒诊断。

• 发表时间: 2006
• 期刊: Research in Legal Medicine 34
• 作者: Akita S;Daian T;Ishihara H;Fujii T;Akino K;Takehiko Takatori;Takehiko Takatori
• 通讯作者: Takehiko Takatori