The Importance of Chirality in Influencing Both Acute and Delayed Neuropathic Toxicity of Organophosphorus Esterst

Triesters (or mixed ester/amides) of phosphoric acid, diesters of organophosphonic acids or monoesters of di-organophosphinic acids may be designed to be stable plasticizers, hydraulic fluids or flame retardants or may be designed as pesticides. In the latter case one ester bond is more labile so that the whole molecule may act as an agent to acylate certain critical targets in vivo. Pesticides are often prepared as derivatives of the analogous phosphorothioic acids which are more stable in storage but are metabolized to the active P=0 compounds (oxons) in vivo. Typical acute toxicity of OP esters arises from inhibition of vital acetylcholinesterase (AChE) which normally hydrolyses neurotransmitter liberated at neural junctions: acetylcholine (ACh) accumulates and causes excessive stimulation of nerves which can become fatal. Organophosphorus-induced delayed polyneuropathy (OPIDP) is caused by some but not all OP esters by acylation and subsequent modification of the structure of a neural protein commonly called NTE (neuropathy target esterase). This modification depends absolutely on “ageing” of inhibited NTE. The attack on either AChE or NTE by OP esters is influenced by steric factors. Thus the inhibitory power of P( —) isomers of soman (pinacolyl methylphosphono-fluoridate) 4against AChE is at least 1000 greater than that of the P(+) isomers. NTE is more easily inhibited by the C( —)P( +) isomer than by the other three. The related reactions of spontaneous reactivation and “ageing” of inhibited esterases are dependent on molecular structure of the phosphyl-enzyme. When NTE is inhibited in vivo by the L( —) isomer of EPN or EPN oxon (4-nitrophenyl ethyl phenylphosphonate), “ageing” of inhibited NTE is rapid and polyneuropathy follows 2 weeks later; when NTE is inhibited by the D(+) isomer, ageing is negligible and dosed animals become resistant to the neuropathic effects (NOT the cholinergic effects) of challenge OP esters. Other examples are presented. Analytical methods which distinguish between isomers of free and target-bound agents and their metabolites are necessary to advance detailed mechanistic studies of intoxication by chiral OP esters.