Winter Michael, Wille Timo, Musilek Kamil, Kuca Kamil, Thiermann Horst, Worek Franz
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
University of Hradec Kralove, Faculty of Science, Department of Chemistry, Hradec Králové, Czech Republic.
Toxicol Lett. 2016 Feb 26;244:136-142. doi: 10.1016/j.toxlet.2015.07.007. Epub 2015 Jul 22.
The limited effectiveness of the established oximes obidoxime and pralidoxime resulted in ongoing research on novel oximes for the reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OP). In order to get more insight into the ability of bispyridinium oximes to reactivate human AChE inhibited by structurally different OP the reactivation kinetics of 31 compounds was determined with tabun-, cyclosarin- and paraoxon-inhibited AChE under identical experimental conditions. The determined affinity (KD), reactivity (kr) and hybrid reactivation rate constants (kr2) enabled theoretical calculations and gave insight into distinct structural features which are important for the reactivation of AChE inhibited by different OP. Several oximes with superior reactivating potency towards selective OP-AChE conjugates were identified but none of the tested oximes can be considered as a broad spectrum reactivator. In the end, the data of this and previous studies gives rise to the question whether further modifications of the bispyridinium structure could ever result in a universal reactivator or whether future research should be directed to different templates.
已有的肟类化合物氯解磷定和碘解磷定效果有限，因此人们持续开展新型肟类化合物的研究，以用于重新激活被有机磷化合物（OP）抑制的乙酰胆碱酯酶（AChE）。为了更深入了解双吡啶肟类化合物重新激活被结构不同的OP抑制的人AChE的能力，在相同实验条件下，测定了31种化合物对被塔崩、环沙林和对氧磷抑制的AChE的重新激活动力学。所测定的亲和力（KD）、反应活性（kr）和混合重新激活速率常数（kr2）可用于理论计算，并深入了解对不同OP抑制的AChE重新激活很重要的独特结构特征。已鉴定出几种对选择性OP-AChE缀合物具有更高重新激活效力的肟类化合物，但所测试的肟类化合物均不能被视为广谱重新激活剂。最后，本研究及之前研究的数据引发了一个问题，即双吡啶结构的进一步修饰是否能产生通用的重新激活剂，或者未来的研究是否应转向不同的模板。
