Progress on the Development of Oxime Derivatives as a Potential Antidote for Organophosphorus Poisoning

Nowadays, organophosphorus poisoning is the most common emergency throughout the world. Two functionally different types of drugs are used in common to treat such intoxication cases. The first type includes the reactivators of acetylcholinesterase (AChE)-oximes, which have the capability to restore the physiological function of inhibited AChE. The second type includes anticholinergic, such as atropine that antagonizes the effects of excessive ACh by blocking muscarinic receptors. Alternatively, anticholinergic and reactivators may be co-administered to get synergistic effects. At muscarinic and nicotinic synapses, organophosphorus compounds inhibit AChE release by phosphoryl group deposition at the enzyme's active site very quickly. AChE regenerative process can be accelerated by detaching the OP compound at -OH group of the enzyme. OP compound combines with the AChE enzyme forming a complex and making it inactive. After ageing of the inactive state of AChE, it is difficult to break the complex to regenerate the enzyme resulting in acetylcholine accumulation at synapses. To counter the effect of OP compound, oximes catalyse the reactivation of active AChE by exerting nucleophilic attack on the phosphoryl group. Oximes theoretically remove OP compound from the complex by acting on phosphoryl bond resulting in enzyme reactivation. Reactivation of AChE inhibited by OP compounds through the above mentioned approach poses certain limitations. There is no universal antidote capable of effectively restoring AChE inhibited by wide-ranging OP compounds. The oxime reactivators are efficient only when administered before the “ageing” of AChE-OP complex. Anticholinergic drugs, like atropine, are effective only on muscarinic receptors but not on nicotinic receptors (nAChRs).

Keywords: Acetylcholine, Acetylcholinesterase, Atropine, Obidoxime, Butyrylcholinesterase, HI-6, Organophoshosphorus, Poisoning: Oxime, Reactivation, 2-PAM.