Synthesis of methylating ligands that reactivate aged acetylcholinesterase

描述（由申请人提供）：有机磷（OP）化学战剂，如沙林和索曼，是急性毒性化合物，分别通过抑制中枢和周围神经系统神经-神经和神经肌肉连接处乙酰胆碱酯酶（AChE）的活性起作用。酶的抑制发生在通常参与催化作用的活性位点丝氨酸亲核试剂的磷酸化。促使政府

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.