Naslov
Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in theraphy against tabun poisoning

Autori
Kovarik, Zrinka ; Čalić, Maja ; Šinko, Goran ; Bosak, Anita ; Lucić Vrdoljak, Ana ; Radić, Božica

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

Izvornik
The IXth International Meeting on Cholinesterases, Suzhou, Kina, Program Book / - , 2007, 45-45

Skup
The IXth Inernational Meeting on Cholinesterases

Mjesto i datum
Suzhou, Kina, 06.05.2007. - 10.05.2007

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
oximes; reactivation; tabun; antidotes; acetylcholinesterase

Sažetak
One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime found as the most effective reactivators have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE and studied their effects on tabun-poisoned mice. Using molecular mechanics we performed conformational analysis to determine the flexibility of the oxime molecules. Tabun-inhibited human erythrocyte AChE was completely reactivated by three flexible bispyridinium oximes with the oxime group in para-position and with the linker of three or four methylene groups. Although oximes with imidazolium ring or with the oxime group in the ortho-position on the pyridinium ring had similar electron density on the oxygen of the oxime group as para-bispyridinium oximes, they did not show significant reactivation potency. However, as inhibitors they had higher affinity for the native human erythrocyte AChE. Promising oximes were further tested in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. Without pretreatment the best antidotal efficacy was obtained with para-oximes that protected mice from 5-fold LD50 of tabun. Pretreatment by the oxime insured survival of all tested animals after the application of 10 LD50 of tabun. Herein we show that already promising treatment in tabun poisoning by oximes and atropine could be improved if oximes are also used in pretreatment. Furthermore, low toxicity of these oximes makes these compounds leading in the therapy of tabun poisoning. Since the reactivating efficacy of the oximes in vitro corresponded to their therapeutic efficacy in vivo, it seems that pharmacological effect of these oximes is indeed primarily related to the reactivation of tabun-phosphorylated AChE.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA