Bartling A, Worek F, Szinicz L, Thiermann H
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
Toxicology. 2007 Apr 20;233(1-3):166-72. doi: 10.1016/j.tox.2006.07.003. Epub 2006 Jul 7.
The pertinent threat of using organophosphorus compound (OP)-type chemical warfare agents (nerve agents) during military conflicts and by non-state actors requires the continuous search for more effective medical countermeasures. OP inhibit acetylcholinesterase (AChE) and therefore standard treatment of respective poisoning includes AChE reactivators (oximes) in combination with antimuscarinic agents. Hereby, standard oximes, 2-PAM and obidoxime, are considered to be rather insufficient against various nerve agents. Numerous experimental oximes have been investigated in the last decades by in vitro and in vivo models. Recently, we studied the reactivating potency of several oximes with human AChE inhibited by structurally different OP and observed remarkable differences depending on the OP and oxime. In order to investigate structure-activity relationships we determined the various kinetic constants (inhibition, reactivation, aging) for a series of sarin analogues bearing a methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, cyclohexyl or pinacolyl group with human AChE and BChE. The rate constants for the inhibition of human erythrocyte AChE and plasma BChE by these OP (k(i)), for the spontaneous dealkylation (k(a)) and reactivation (k(s)) of OP-inhibited AChE and BChE as well as for the oxime-induced reactivation of OP-inhibited AChE and BChE by the oximes obidoxime, 2-PAM, HI 6, HLö 7 and MMB-4 were determined. With compounds bearing a n-alkyl group the inhibition rate constant increased with chain length. A relation between chain length and spontaneous reactivation velocity was also observed. In contrast, no structure-activity dependence could be observed for the oxime-induced reactivation of AChE and BChE inhibited by the compounds tested. In general, OP-inhibited AChE and BChE were susceptible towards reactivation by oximes. HLö 7 was the most potent reactivator followed by HI 6 and obidoxime while 2-PAM and MMB-4 were rather weak reactivators. These data indicate a potential structure-activity relationship concerning inhibition and spontaneous reactivation but not for oxime-induced reactivation.
在军事冲突期间以及非国家行为者使用有机磷化合物（OP）类化学战剂（神经毒剂）构成的相关威胁，要求持续寻找更有效的医学应对措施。OP会抑制乙酰胆碱酯酶（AChE），因此相应中毒的标准治疗包括使用AChE复活剂（肟类）与抗毒蕈碱剂联合使用。在此，标准肟类药物2-解磷定和双复磷被认为对各种神经毒剂的效果相当不足。在过去几十年中，通过体外和体内模型对众多实验性肟类进行了研究。最近，我们研究了几种肟类对被结构不同的OP抑制的人AChE的复活效力，并观察到根据OP和肟类的不同存在显著差异。为了研究构效关系，我们测定了一系列带有甲基、乙基、正丙基、正丁基、异丙基、异丁基、环己基或频哪基的沙林类似物与人AChE和丁酰胆碱酯酶（BChE）的各种动力学常数（抑制、复活、老化）。测定了这些OP对人红细胞AChE和血浆BChE的抑制速率常数（k(i)）、OP抑制的AChE和BChE的自发脱烷基化速率常数（k(a)）和复活速率常数（k(s)），以及肟类药物双复磷（obidoxime）、2-解磷定（2-PAM）、HI 6、HLö 7和MMB-4对OP抑制的AChE和BChE的肟类诱导复活速率常数。对于带有正烷基的化合物，抑制速率常数随链长增加。还观察到链长与自发复活速度之间的关系。相比之下，对于所测试化合物抑制的AChE和BChE的肟类诱导复活，未观察到构效依赖性。总体而言，OP抑制的AChE和BChE对肟类诱导的复活敏感。HLö 7是最有效的复活剂，其次是HI 6和双复磷，而2-解磷定和MMB-4是较弱的复活剂。这些数据表明在抑制和自发复活方面存在潜在的构效关系，但在肟类诱导复活方面不存在。
