Evaluation of four novel hydroxypicolinaldehyde oximes as efficient uncharged reactivators of VX-inhibited human acetylcholinesterase (CROSBI ID 620775)
Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Kovarik, Zrinka ; Katalinić, Maja ; Jean, Ludovic ; Renard, Pierre-Yves ; Renou, Julien ; Gomez, Catherine
engleski
Evaluation of four novel hydroxypicolinaldehyde oximes as efficient uncharged reactivators of VX-inhibited human acetylcholinesterase
Organophosphates (OP) inhibit acetylcholinesterase (AChE, EC 3.1.1.7), both in peripheral tissues and the central nervous system, causing adverse and sometimes fatal effects due to the accumulation of the neurotransmitter acetylcholine. The currently used therapy, which focuses on the reactivation of inhibited AChE, is limited to peripheral tissues because the commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier at therapeutically relevant levels. Three new uncharged oximes 1 [E)-3-hydroxy-6-(4-morpholinobutyl)picolinaldehyde oxime], 2 [(E)-6-(5-(diethylamino)pentyl)-3-hydroxypicolinaldehyde oxime], and 3[(Z)-3-hydroxy-6-(5-(piperidin-1-yl)pentyl)picolinaldehyde oxime] have been synthesized. These novel compounds exhibited in vitro reactivation potencies toward VX-phosphorylated human acetylcholinesterase equal or superior to those of pyridinium oximes (HI-6, 2PAM, etc.), which are currently used as antidotes against nerve agents. The evaluation of individual reactivation constants revealed that the potent reactivation exhibited by oxime 1 referred to its efficient interaction with the phosphonate group of the VX-conjugated AChE through forming a transition state reflected in an up to 2-times faster k+2 than HI-6. Interestingly, the binding affinity of the other two oximes was very similar to that of HI-6, meaning that the structural requirements of novel compounds to react with phosphorylated AChE were fulfilled. In conclusion, we obtained potential antidotes for OP-poisoning that could act centrally, reactivating brain OP-phosphorylated AChE.
in vitro reactivation; kinetic parameters
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Podaci o prilogu
279-x.
2014.
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objavljeno
Podaci o matičnoj publikaciji
The FEBS journal
1742-464X
Podaci o skupu
The FEBS EMBO 2014 Conference
poster
30.08.2014-04.09.2014
Pariz, Francuska