We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, obidoxime, methoxime, trimedoxime and HI-6) to reactivate human acetylcholinesterase (AChE), inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos). We also tested reactivation of human butyrylcholinesterase (BChE) with the aim of finding a potent oxime, suitable to serve as a "pseudocatalytic" bioscavenger in combination with this enzyme. Such a combination could allow an increase of prophylactic and therapeutic efficacy of the administered enzyme. According to our results, the best broad-spectrum AChE reactivators were trimedoxime and obidoxime in the case of paraoxon, leptophos-oxon, and methamidophos-inhibited AChE. Methamidophos and leptophos-oxon were quite easily reactivatable by all tested reactivators. In the case of methamidophos-inhibited AChE, the lower oxime concentration (10(-5) M) had higher reactivation ability than the 10(-4) M concentration. Therefore, we evaluated the reactivation ability of obidoxime in a concentration range of 10(-3)-10(-7) M. The reactivation of methamidophos-inhibited AChE with different obidoxime concentrations resulted in a bell shaped curve with maximum reactivation at 10(-5) M. In the case of BChE, no reactivator exceeded 15% reactivation ability and therefore none of the oximes can be recommended as a candidate for "pseudocatalytic" bioscavengers with BChE.

• Keywords
• acetylcholinesterase, butyrylcholinesterase, in vitro, nerve agent, organophosphate, oxime, pesticide, reactivator, scavenger,
• MeSH
• Acetylcholinesterase chemistry   metabolism   MeSH
• Butyrylcholinesterase chemistry   metabolism   MeSH
• Cholinesterase Inhibitors chemistry   metabolism   MeSH
• Erythrocytes enzymology   MeSH
• Humans MeSH
• Organophosphorus Compounds chemistry   metabolism   MeSH
• Oximes chemistry   MeSH
• Pesticides chemistry   metabolism   MeSH
• Cholinesterase Reactivators chemistry   metabolism   MeSH
• Protein Binding MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Pesticides MeSH
• Cholinesterase Reactivators MeSH

Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun- and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027).

• MeSH
• Acetylcholinesterase MeSH
• Humans MeSH
• Organophosphates antagonists & inhibitors   MeSH
• Organophosphorus Compounds antagonists & inhibitors   MeSH
• Oximes chemical synthesis   MeSH
• Pyridinium Compounds chemical synthesis   MeSH
• Cholinesterase Reactivators chemical synthesis   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-(4-hydroxyiminomethylpyridinium)-3-pyridiniumpropane MeSH Browser
• Acetylcholinesterase MeSH
• cyclohexyl methylphosphonofluoridate MeSH Browser
• Organophosphates MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser

In this work, two oximes for the treatment of tabun-inhibited acetylcholinesterase (AChE; EC 3.1.1.7), K074 (1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide) and K075 ((E)-1,4-bis(4-hydroxyiminomethylpyridinium)but-2-en dibromide), were tested in vitro as reactivators of AChE. Comparison was made with currently used AChE reactivators (pralidoxime, HI-6, methoxime and obidoxime). Human brain homogenate was taken as an appropriate source of the cholinesterases. As resulted, oxime K074 appears to be the most potent reactivator of tabun-inhibited AChE, with reactivation potency comparable to that of obidoxime. A second AChE reactivator, K075, does not attain as great a reactivation potency as K074, although its maximal reactivation (17%) was achieved at relevant concentrations for humans.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation drug effects   MeSH
• Butanes chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Humans MeSH
• Caudate Nucleus drug effects   enzymology   MeSH
• Obidoxime Chloride chemistry   pharmacology   MeSH
• Organophosphates toxicity   MeSH
• Oximes chemistry   pharmacology   MeSH
• Pralidoxime Compounds chemistry   pharmacology   MeSH
• Pyridinium Compounds chemistry   pharmacology   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• In Vitro Techniques MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide MeSH Browser
• Acetylcholinesterase MeSH
• asoxime chloride MeSH Browser
• Butanes MeSH
• Cholinesterase Inhibitors MeSH
• K075 compound MeSH Browser
• N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Browser
• Obidoxime Chloride MeSH
• Organophosphates MeSH
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser