engleski

Reactivation of inhibited acetylcholinesterase with newly synthesized chlorinated pyridinium aldoximes

Acetylcholinesterase (AChE) is an essential enzyme that hydrolyses neurotransmitter acetylcholine (ACh) and is important in the control of neurotransmission in the neuromuscular and brain synapses. Organophosphorus (OP) compounds (i.e. nerve agents and pesticides) irreversibly inhibit AChE. Consequently, ACh accumulates in the synapses and overstimulates ACh receptors, which can result in a lethal outcome due to respiratory arrest. Therapy in OP poisoning comprises atropine (antimuscarinic drug), an oxime reactivator of OP-inhibited AChE, and an anticonvulsant drug. The standard oximes used in practice are not equally efficient in the reactivation of different OP-AChE conjugates. Morover, they do not cross the blood-brain barrier (BBB) and thus, they do not reactivate brain AChE. Newly synthesized mono- and bis- chlorinated bispyridinium aldoximes were designed in order to keep some structural characteristics of previously reported non- chlorinated analogues that have been proven potent in the reactivation of inhibited AChE, especially for tabun-inhibited AChE. An additional premise in their design was that the addition of chlorine atom would slightly increase the lipophilicity of these compounds in comparison to their analogues that cross the BBB at up to 6 % of their blood concentration. Therefore, it is expected that these oximes would achieve higher concentration in the brain. The reactivation potency of the oximes was evaluated for AChE inhibited by various nerve agents (sarin, cyclosarin, VX, tabun) and pesticide analogue (paraoxon) and compared to analogous oximes. Although all six of the new oximes showed promising potency to reactivate OP-inhibited AChE, one oxime was proven as an extremely potent reactivator of AChE in case of cyclosarin, sarin and VX inhibition. Along with its predicted lipophilicity, this oxime is anticipated as both peripherally and centrally active reactivator. This work was supported by the Croatian Science Foundation (4307) and Czech Grant Agency (18-01734S).

organophosphorus poisoning, chlorinated oximes, centrally active reactictivators

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