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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

Kovarik, Zrinka ; Katalinić, Maja ; Jean, Ludovic ; Renard, Pierre-Yves ; Renou, Julien ; Gomez, Catherine Evaluation of four novel hydroxypicolinaldehyde oximes as efficient uncharged reactivators of VX-inhibited human acetylcholinesterase // The FEBS journal. 2014. str. 279-x

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

Povezanost rada

Kemija

Indeksiranost