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

INTRODUCTION: Organophosphorus nerve agents inhibit the enzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators (also known as oximes) are generally used for the reactivation of an inhibited enzyme. METHODS: Two new AChE reactivators--K033 and K027--were tested for their in vitro reactivation of sarin-inhibited pig-brain AChE. Their reactivation potencies were compared with the commercially available AChE reactivators, pralidoxime, obidoxime, and HI-6. RESULTS: Of the oximes tested, the newly developed oxime K027 achieved the highest reactivation potency (100%; concentration of the oxime -10(-2) M). However, oxime HI-6 (33%) and obidoxime (23%) seem to be the best AChE reactivators for human relevant doses (10(-4) M and lower). CONCLUSION: For human relevant doses, newly developed oximes (K027 and K033) do not surpass the reactivation potency of the most promising oxime, HI-6.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes pharmacology   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Brain drug effects   enzymology   MeSH
• Obidoxime Chloride pharmacology   MeSH
• Oximes pharmacology   MeSH
• Pralidoxime Compounds pharmacology   MeSH
• Swine MeSH
• Pyridinium Compounds pharmacology   MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• Sarin toxicity   MeSH
• In Vitro Techniques MeSH
• Research Design MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
• 1,4-bis(2-hydroxyiminomethylpyridinium)butane MeSH Browser
• Acetylcholinesterase MeSH
• Antidotes MeSH
• asoxime chloride MeSH Browser
• Cholinesterase Inhibitors MeSH
• Obidoxime Chloride MeSH
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• Sarin MeSH

We investigated the relationship between the chemical structure of acetylcholinesterase (AChE; EC 3.1.1.7) reactivators and their potency in reactivating this enzyme, after prior inhibition by VX (O-ethyl-S-(2-diisopropylaminoethyl)-methylthiophosphonate), tabun, sarin, and cyclosarin. The oximes, pralidoxime (2-PAM), HI-6 [1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxa-propane dichloride], obidoxime and HS-6 [1-(2-hydroxyiminomethylpyridinium)-3-(3-carbamoylpyridinium)-2-oxa-propane dichloride] were used as representatives of the group of AChE reactivators. Rat brain AChE was used as the appropriate source of the enzyme. Our results confirm that there is no single broad-spectrum oxime suitable for the treatment of poisoning with all highly toxic organophosphorus agents.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation drug effects   physiology   MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Rats MeSH
• Brain drug effects   enzymology   MeSH
• Organophosphates pharmacology   MeSH
• Oximes pharmacology   MeSH
• Pyridinium Compounds pharmacology   MeSH
• Cholinesterase Reactivators pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphates MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH