Reactivation of Cyclosarin-inhibited Rat Brain Acetylcholinesterase by Pyridinium–Oximes

Abstract

Cyclohexyl methylphosphonofluoridate (cyclosarin, cyclosin, GF) is a highly toxic organophosphate, which is resistant to conventional oxime therapy. To gain insight into the reactivation kinetics, rat brain acetylcholinesterase (AChE) was inhibited in vitro by cyclosarin (pH 8.0, 25 degrees C) and reactivated with 22 different pyridiniumoximes. Three compounds were shown to be superior to the other oximes: 4-carbamoyl-4'-[(hydroxyimino)methyl]-1,1'-(oxydimethylene)dipyridin-1-ium dichloride (HS-6), 4'-carbamoyl-2-[(hydroxyimino)methyl]-1,1'-(oxydimethylene)dipyridin-1-ium dichloride (HI-6), and 4'-carbamoyl-2-[(hydroxyimino)-methyl]-1,1'-(but-2-ene-1,4-diyl)dipyridin-1-ium dichloride (BI-6).

Reactivation Potency of New Group of Acetylcholinesterase Reactivators and Their Comparison with Currently Available Oximes

“…Moreover, it is clear from the results that reactivators with oxime group at the position two are the most potent reactivators of cyclosarin-inhibited AChE. These results are in good agreement with our previous results (9,11).…”

“…Due to this fact, many laboratories throughout the world are interested in the synthesis of new AChE reactivators with better reactivation potency (2,8,(9)(10)(11)(12)(13)(14)(15). There were synthesized new reactivators differing in the number of quaternary pyridinium rings, in the length of the connection chain between pyridinium rings, presence of other heteroarenium rings, using of different functional groups or in the presence and position of oxime groups.…”

Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes

“…For example, pralidoxime is unable to reactivate tabun-inhibited and cyclosarin-inhibited AChE in vitro and in vivo [6][7][8]. Similar results were obtained for obidoxime.…”

“…The chemical structure of AChE reactivators affects their ability to reactivate AChE inhibited by nerve agents [6,8]. Some of the most important moieties include the presence of the oxime group, the presence of quaternary nitrogen, and the appropriate length of the connection chain between both quaternary nitrogens [27].…”

Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase

“…pralidoxime -"the golden standard of AChE reactivators" (1, 2-hydroxyiminomethyl-1-methylpyridinium chloride), oxime HI-6 (2, 1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride), obidoxime (3, Toxogonine w , 1,3-bis(4-hydroxyiminomethyl-pyridinium)-2-oxapropane dichloride) ( Figure 1) [8][9][10][11]. Nevertheless, every type of OP needs a specific structure for the AChE reactivator and there is not a broad spectrum reactivator after more than fifty years of investigations [12][13][14][15]. Therefore, the development and selection of new effective reactivators of AChE-like antidotes of OP are very important.…”