Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.

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Pang YP, Kollmeyer TM, Hong F, Lee JC, Hammond PI, Haugabouk SP, Brimijoin S

Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.

Chem Biol. 2003 Jun;10(6):491-502.

PubMed ID

12837382 [ View in PubMed

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Abstract

To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Isoflurophate	Acetylcholinesterase	Protein	Humans	Yes	Inhibitor	Details