Naslov
Evaluation of four novel hydroxypicolinaldehyde oximes as efficient uncharged reactivators of VX-inhibited human acetylcholinesterase

Autori
Kovarik, Zrinka ; Katalinić, Maja ; Jean, Ludovic ; Renard, Pierre-Yves ; Renou, Julien ; Gomez, Catherine

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
FEBS Journal 281 (Suppl. 1) / - , 2014

Skup
The FEBS EMBO 2014 Conference

Mjesto i datum
Pariz, Francuska, 30.08.2014. - 04.09.2014

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
in vitro reactivation; kinetic parameters

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA