A COMPLEX PROCESS OF THE DEVELOPMENT OF NEW ACETYLCHOLINESTERASE REACTIVATORS- FROM PREDICTION TO IN VIVO EVALUATION

The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the irreversible inhibition of acetylcholinesterase that is followed by an accumulation of acetylcholine at peripheral and central cholinergic synapses, which in turn leads to the clinical manifestation of various signs and symptoms summarized as acute cholinergic crisis. Nerve agent poisoning is commonly treated using a combination of a cholinolytic drug to counteract the accumulation of acetylcholine at muscarinic receptors and acetylcholinesterase reactivators (pralidoxime or obidoxime) to reactivate nerve agent-inhibited acetylcholinesterase. There is a strong interest in developing new, more potent acetylcholinesterase reactivators. The development of acetylcholinesterase reactivators consists of several steps: description of nerve agent intoxication mechanism on molecular basis (molecular design), prediction of biologically active structure of acetylcholinesterase reactivators (artificial neural networks), their synthesis, in vitro and in vivo evaluation of their potency to counteract acute toxicity of nerve agents