Kinetic analysis of interactions of amodiaquine with human cholinesterases and organophosphorus compounds. (30th March 2016) - Bierwisch, Anne
Highlights: We investigated the interaction of human cholinesterases, OP nerve agents and amodiaquine. Amodiaquine is a potent inhibitor of human AChE and to less extent of human BChE. Amodiaquine resulted in slow and partial reactivation of sarin-, cyclosarin- and VX-inhibited AChE and BChE. Amodiaquine may be considered as a template for further non-oxime reactivators. Abstract: Standard therapy of poisoning by organophosphorus compounds (OP) is a combined administration of an anti-muscarinic drug ( e . g . atropine) and an oxime as reactivator of inhibited acetylcholinesterase (AChE). Limited efficacy of clinically used oximes against a variety of OPs was shown in numerous studies, calling for research on novel reactivators of OP-inhibited AChE. Recently, reactivation of OP-inhibited AChE by the antimalarial drug amodiaquine was reported. In the present study, amodiaquine and its interactions with human cholinesterases in presence or absence of OP nerve agents was investigated in vitro . Thereby, reversible inhibition of human cholinesterases by amodiaquine (AChE ≫ BChE) was observed. Additionally, a mixed competitive-non-competitive inhibition type of amodiaquine with human AChE was determined. Slow and partial reactivation of sarin-, cyclosarin- and VX-inhibited cholinesterases by amodiaquine was recorded, amodiaquine failed to reactivate tabun-inhibited human cholinesterases. Amodiaquine, being a potent, reversible AChE inhibitor, was tested for its potential benefit as a pretreatment to prevent complete irreversible AChE inhibition by the nerve agent soman. Hereby, amodiaquine failed to prevent phosphonylation and resulted only in a slight increase of AChE activity after removal of amodiaquine and soman. At present the molecular mechanism of amodiaquine-induced reactivation of OP-inhibited AChE is not known, nevertheless amodiaquine could be considered as a template for the design of more potent non-oxime reactivators.