Bundeswehr Institute of Pharmacology and Toxicology, D-80937 Munich, Germany.
Molecules. 2020 Jul 2;25(13):3029. doi: 10.3390/molecules25133029.
The implementation of the Chemical Weapons Convention (CWC) in 1997 was a milestone in the prohibition of chemical warfare agents (CWA). Yet, the repeated use of CWA underlines the ongoing threat to the population. Organophosphorus (OP) nerve agents still represent the most toxic CWA subgroup. Defensive research on nerve agents is mainly focused on the "classical five", namely tabun, sarin, soman, cyclosarin and VX, although Schedule 1 of the CWC covers an unforeseeable number of homologues. Likewise, an uncounted number of OP pesticides have been produced in previous decades. Our aim was to determine the in vitro inhibition kinetics of selected organophosphono- and organophosphorothioates with human AChE, as well as hydrolysis of the agents in human plasma and reactivation of inhibited AChE, in order to derive potential structure-activity relationships. The investigation of the interactions of selected OP compounds belonging to schedule 1 (V-agents) and schedule 2 (amiton) of the CWC with human AChE revealed distinct structural effects of the -alkyl, --alkyl and ,-dialkyl residues on the inhibitory potency of the agents. Irrespective of structural modifications, all tested V-agents presented as highly potent AChE inhibitors. The high stability of the tested agents in human plasma will most likely result in long-lasting poisoning in vivo, having relevant consequences for the treatment regimen. In conclusion, the results of this study emphasize the need to investigate the biological effects of nerve agent analogues in order to assess the efficacy of available medical countermeasures.
1997 年《化学武器公约》的实施是禁止化学战剂（CWA）的一个里程碑。然而，CWA 的反复使用突显了对民众的持续威胁。有机磷（OP）神经毒剂仍然是最毒的 CWA 亚组。神经毒剂的防御性研究主要集中在“经典五毒”，即塔崩、沙林、梭曼、环沙林和 VX，尽管《化学武器公约》附表 1 涵盖了数量不可预见的同系物。同样，在过去几十年中也生产了数量无法计数的 OP 农药。我们的目的是确定选定的有机膦酸酯和有机硫代膦酸酯与人乙酰胆碱酯酶的体外抑制动力学，以及在人血浆中的水解和抑制的乙酰胆碱酯酶的重新激活，以得出潜在的结构-活性关系。对属于《化学武器公约》附表 1（V 剂）和附表 2（阿米妥）的选定 OP 化合物与人类 AChE 的相互作用的研究表明，-烷基、--烷基和，-二烷基残基对这些化合物的抑制效力具有明显的结构影响。无论结构如何修饰，所有测试的 V 剂都表现出作为高度有效的 AChE 抑制剂。在人血浆中测试的所有这些化合物的高稳定性很可能导致体内持久中毒，对治疗方案有相关影响。总之，本研究的结果强调了有必要研究神经毒剂类似物的生物学效应，以评估现有医疗对策的疗效。
