From Pyridinium-based to Centrally Active Acetylcholinesterase Reactivators

Abstract

Organophosphates are used as pesticides or misused as warfare nerve agents. Exposure to them can be fatal and death is usually caused by respiratory arrest. For almost six decades, pyridinium oximes represent a therapeutic tool used for the management of poisoning with organophosphorus (OP) compounds. However, these compounds possess several drawbacks. Firstly, they are inefficient in the restoration of brain acetylcholinesterase (AChE) activity due to a hard blood-brain barrier penetration. Secondly, there is no broad-spectrum AChE reactivator. Lastly, none of the oximes can reactivate "aged" AChE. In this context, uncharged reactivators represent a new hope in a way of increased bioavailability in the central compartment and better therapeutic management of the OP poisoning.

Avaliação da atividade de aldeídos aromáticos e suas oximas frente à enzima acetilcolinesterase eritrocitária humana

“…O grupo oxima atua como reativador da AChE quando esta encontra-se inibida por organofosforados, através do ataque nucleofílico ao átomo de fósforo do resíduo de serina fosforilado da AChE, resultando na remoção do grupo fosforil e na consequente reativação da enzima inibida (Korabecnya et al, 2014;Araújo et al, 2016). Este processo depende da nucleofilicidade e orientação do grupo oxima na molécula do reativador, assim como da força das interações intermoleculares formadas entre a enzima e o organofosforado, de modo que sua eficácia pode variar de acordo com o organofosforado utilizado (Costa et al, 2011;Kassa et al, 2015).…”

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

“…The reactivation rate is dependent on the structure of the phosphoryl moiety, source of enzyme, concentration of oximes, aging rate, and the stearic hindrance effects between oxime molecule and the phosphoryl moiety attached to the active site of AChE. 4,11,36,43 Since the pyridinium oximes are polar organic compounds with large negative lipophilicity values, they are difficult to penetrate the BBB. Currently, several approaches are being considered in order to improve the potency of oximes to reactivate AChE.…”

“…OP poisonings involve the inhibition of enzyme acetylcholinesterase (AChE) that physiologically plays an important role in neurotransmission. [10][11][12] This will result in the overstimulation of cholinergic receptors by acetylcholine (ACh) which will occur in the peripheral nervous system, central nervous system (CNS) and at neuromuscular junctions causing cholinergic crises, seizures, respiratory arrest, bronchorrhea and ultimately lead to fatal consequences. 13,14 Current treatment of OP poisonings consists of the administration of a muscarinic receptor antagonist (e.g.…”

HLö-7 - A REVIEW OF ACETYLCHOLINESTERASE REACTIVATOR AGAINST ORGANOPHOSPHOROUS INTOXICATION

“…9). 6,[28][29][30] 75 Uncharged reactivators represent a new hope in the therapy of OP intoxication. However, their potential implication in the OP-countermeasure is still on the long road ahead.…”