engleski

In vitro evaluation of uncharged oximes for organophosphorus nerve agent poisoning

Organophosphorus nerve agents (OPNA ; e.g. sarin, cyclosarin, tabun, VX) are lethal compounds that act on cholinergic nervous system by irreversible inhibition of acetylcholinesterase (AChE, E.C. 3.1.1.7) and butyrylcholinesterase (BChE, E.C. 3.1.1.8). Such an inhibition causes accumulation of the synaptic acetylcholine (ACh) and overstimulation of muscarinic and nicotinic receptors in the peripheral and central nervous system (CNS). Poisoning leads to respiratory failure and seizures, while those who survive experience long-term neurological and neuropsychiatric disorders. In light of the growing risk of terrorist attacks in Europe and worldwide, a growing need for adequate protection and proper safety plans has arisen. Current therapeutic approach consists of antimuscarinic atropine, oxime reactivator of acetylcholinesterase and anticonvulsive diazepam. Standard oximes (e.g. 2-PAM, HI-6, obidoxime) are not efficient for every OPNA and they do not possess a possibly preferred pharmacokinetic profile, i.e. their penetration across brain-blood barrier (BBB) is not more than 10 % of the blood concentration. Since standard oxime reactivators are charged, novel uncharged oximes have been synthesised to obtain more efficient reactivators with enhanced CNS penetration capabilities. Four out of seven novel oximes (JR585, JR595, RM048, and GM415) showed a highly promising in vitro reactivation profile of AChE and/or BChE- inhibited by different OPNA. The best results were obtained in the reactivation of VX- inhibited AChE/BChE, sarin-inhibited AChE and cyclosarin-inhibited BChE. Their increased lipophilicity (ClogP = 3.24 – 4.99) and other in silico determined molecular descriptors suggest a better penetration across plasma membranes and a higher volume of distribution (Vd), which implies potential and beneficial reactivation of AChE in the brain. However, a higher incidence of adverse in vivo effects is also predicted by computational studies. Therefore, further evaluation of their in vivo efficacy will include both antidotal and toxicity testing in mice. This work was supported by the COGITO Croatian-French bilateral grant (2015-2016) and by the Croatian Science Foundation grant (no. 4307).

sarin ; cyclosarin ; tabun ; VX ; reactivation

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