Peripheral site ligand-oxime conjugates: A novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase.
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.
TNO Defence, Security and Safety, PO Box 45, 2280 AA Rijswijk, The Netherlands. m.dekoning@tno.nl
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de Koning
M J A
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Joosen
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Noort
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van Zuylen
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Tromp
D000110:Acetylcholinesterase / Q000187:drug effects*; D001812:Blood-Brain Barrier; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010091:Oximes / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D008024:Ligands; D010091:Oximes; D000110:Acetylcholinesterase