Study of para-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase

ACS Med Chem Lett. 2017 May 8;8(6):622-627. doi: 10.1021/acsmedchemlett.7b00037. eCollection 2017 Jun 8.


Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed.

Keywords: Acetylcholinesterase; organophosphorus chemical nerve agents; quinone methide.