Synthesis of methylating ligands that reactivate aged acetylcholinesterase

说明（由申请人提供）：沙林和梭曼等有机磷化学战剂是急性毒性化合物，通过抑制中枢和外周神经系统神经-神经和神经肌肉接头处乙酰胆碱酯酶的活性发挥作用。酶的抑制作用是通过磷酸化活性位点丝氨酸亲核体而发生的，丝氨酸亲核体通常参与催化作用。及时给药 肟类化合物可导致磷酸-乙酰胆碱酯酶加合物的脱磷酸化，因此是一种解毒策略。然而，特别是对于化学战剂梭曼，最初的磷酰-AChE加合物经历脱烷基化反应，导致所谓的老化加合物，对此没有已知的解毒剂。本申请提出通过合成和评估AChE配体来解决这个令人困惑的问题，所述AChE配体可以结合在老化的酶加合物的活性位点中，并且随后用作甲基转移剂以使老化的酶再烷基化。这反过来又会恢复加合物对肟亲核脱磷酸的敏感性，从而导致酶活性的恢复。因此，这一奋进的成功应该为开发针对目前难治性OP化学战剂的解毒剂治疗的有效药物打开大门。 公共卫生相关性：本申请致力于合成和评价乙酰胆碱酯酶的配体，其可用作对抗有机磷（OP）化学战剂的解毒剂。开展这项工作的动机是担心恐怖组织可能企图利用这些制剂造成大规模伤亡。预计随着OP药剂解毒剂治疗的改进，这些药剂对我们社会造成的健康和安全风险将得到改善。

DESCRIPTION (provided by applicant): Organophosphorus (OP) chemical warfare agents, such as sarin and soman, are acutely toxic compounds that act by inhibiting the activity of the enzyme acetylcholinesterase (AChE) at nerve-nerve and neuromuscular junctions in the central and peripheral nervous systems, respectively. Inhibition of the enzyme occurs by phosphylation of the active site serine nucleophile that is normally involved in catalysis. Prompt administration of oximes can lead to dephosphylation of the phosphyl-AChE adduct and hence is an antidote strategy. However, and particularly with the chemical warfare agent soman, the initial phosphyl-AChE adduct undergoes a dealkylation reaction that leads to what is called the aged adduct, for which there is no known antidote. This application proposes to address this perplexing problem by synthesis and evaluation of AChE ligands that can bind in the active site of the aged enzyme adduct, and subsequently serve as methyl transfer agents to realkylate the aged enzyme. This in turn will resurrect the susceptibility of the adduct to nucleophilic dephosphylation by oximes and hence lead to recovery of enzyme activity. Success in this endeavor should therefore open the door to the development of efficacious drugs for antidote therapy against currently intractable OP chemical warfare agents. PUBLIC HEALTH RELEVANCE: This application endeavors to synthesize and evaluate ligands of the enzyme acetylcholinesterase that can serve as antidotes against organophosphorus (OP) chemical warfare agents. This work is motivated by the concern that terrorist organizations may aspire to inflict mass casualties by use of these agents. It is anticipated that as OP agent antidote therapy improves, the health and security risks that these agents pose to our society will be ameliorated.