Abstract
Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / drug effects*
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Animals
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Brain / enzymology
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Cholinesterase Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Drug Design
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Drug Evaluation, Preclinical
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Enzyme Activation / drug effects
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Enzyme Activators / chemical synthesis
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Enzyme Activators / chemistry
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Enzyme Activators / pharmacology*
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Models, Biological*
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Molecular Structure
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Organophosphates / antagonists & inhibitors*
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Organophosphates / pharmacology
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Paraoxon / antagonists & inhibitors*
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Paraoxon / pharmacology
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Pyridinium Compounds / chemical synthesis
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Pyridinium Compounds / chemistry
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Pyridinium Compounds / pharmacology*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Cholinesterase Inhibitors
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Enzyme Activators
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Organophosphates
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Pyridinium Compounds
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Acetylcholinesterase
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Paraoxon
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tabun