Peripheral site ligand-oxime conjugates: A novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase

被引：38

作者：

de Koning, M. C. ^{[1
]}

Joosen, M. J. A. ^{[1
]}

Noort, D. ^{[1
]}

van Zuylen, A. ^{[1
]}

Tromp, M. C. ^{[1
]}

机构：

[1] TNO Def Secur & Safety, NL-2280 AA Rijswijk, Netherlands

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 01期

关键词：

Acetylcholinesterase; Oxime; Reactivation; Nerve agent; Peripheral site; NONQUATERNARY CHOLINESTERASE REACTIVATORS; BLOOD-BRAIN-BARRIER; DIALKYLAMINOALKYL THIOESTERS; ETHYL METHYLPHOSPHONYL; CLICK CHEMISTRY; IN-SITU; INVITRO; DERIVATIVES; ANTIDOTES; BINDING;

D O I：

10.1016/j.bmc.2010.10.059

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A conceptually novel approach to the design of reactivators of nerve agent-inhibited acetylcholinesterase (AChE) is presented. The concept comprises the linkage of a peripheral site ligand via a spacer to a reactivating moiety with the eventual goal to develop non-ionic reactivators with sufficient affinity for AChE to induce reactivation and potentially improved blood-brain barrier penetration. Herein, the first step towards that goal-the synthesis and biological evaluation of a peripheral site ligand conjugated to a charged pyridinium oxime is discussed. It was found, that the introduction of the peripheral site ligand not only increased affinity of the construct for AChE but also enhanced reactivation of nerve agent-inhibited AChE. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：588 / 594

页数：7

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