Evaluation of high-affinity phenyltetrahydroisoquinoline aldoximes, linked through anti-triazoles, as reactivators of phosphylated cholinesterases. (15th March 2020)

• Record Type: Journal Article
• Authors: Maček Hrvat, Nikolina; Kalisiak, Jarosław; Šinko, Goran; Radić, Zoran; Sharpless, K. Barry; Taylor, Palmer; Kovarik, Zrinka
• Is Part Of: Toxicology letters. Volume 321(2020)
• Page Start: 83
• Page End: 89
• Publication Date: 2020-03-15
• Subjects: Organophosphate -- Antidote -- Nerve agent -- Acetylcholinesterase -- Butyrylcholinesterase -- Pralidoxime -- Peripheral anionic site; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.12.016
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Phenyltetrahydroisoquinoline moiety acts as peripheral anionic site ligand. Potential reactivators of phosphylated BChE were identified. High binding affinity of AChE for oximes does not ensure efficient reactivation in situ . Oxime efficacy depends on the organophosphate conjugated to the cholinesterase. Abstract: Acetylcholinesterase (AChE) is a pivotal enzyme in neurotransmission. Its inhibition leads to cholinergic crises and could ultimately result in death. A related enzyme, butyrylcholinesterase (BChE), may act in the CNS as a co-regulator in terminating nerve impulses and is a natural plasma scavenger upon exposure to organophosphate (OP) nerve agents that irreversibly inhibit both enzymes. With the aim of improving reactivation of cholinesterases phosphylated by nerve agents sarin, VX, cyclosarin, and tabun, ten phenyltetrahydroisoquinoline (PIQ) aldoximes were synthesized by Huisgen 1, 3 dipolar cycloaddition between alkyne- and azide-building blocks. The PIQ moiety may serve as a peripheral site anchor positioning the aldoxime moiety at the AChE active site. In terms of evaluated dissociation inhibition constants, the aldoximes could be characterized as high-affinity ligands. Nevertheless, high binding affinity of these oximes to AChE or its phosphylated conjugates did not assure rapid and selective AChE reactivation. Rather, potential reactivators of phosphylated BChE, with its enlarged acyl pocket, were identified, especially in case of cyclosarin, where the reactivation rates of the lead reactivator was 100- and 6-times that of 2-PAM and HI-6, respectively. Nevertheless, the return of the enzyme activity was affected by the nerve agent conjugated to catalytic serine, which highlights the lack of the universality of reactivators with respect to both the target enzyme and OP structure.