From Pyridinium-based to Centrally Active Acetylcholinesterase Reactivators
Jan Korabecny, Ondrej Soukup, Rafael Dolezal, Katarina Spilovska, Eugenie Nepovimova, Martin Andrs, Thuy Duong Nguyen, Daniel Jun, Kamil Musilek, Marta Kucerova-Chlupacova and Kamil Kuca
Affiliation: University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Keywords: Acetylcholinesterase, HI-6, organophosphorus compounds, pyridinium oximes, pralidoxime, reactivator, trimedoxime,
Organophosphates are used as pesticides or misused as warfare nerve agents. Exposure to them can be fatal and
death is usually caused by respiratory arrest. For almost six decades, pyridinium oximes represent a therapeutic tool used
for the management of poisoning with organophosphorus (OP) compounds. However, these compounds possess several
drawbacks. Firstly, they are inefficient in the restoration of brain acetylcholinesterase (AChE) activity due to a hard
blood-brain barrier penetration. Secondly, there is no broad-spectrum AChE reactivator. Lastly, none of the oximes can
reactivate “aged” AChE. In this context, uncharged reactivators represent a new hope in a way of increased bioavailability
in the central compartment and better therapeutic management of the OP poisoning.
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