COMPARATIVE-STUDIES OF O,O-DIALKYL-O-CHLOROMETHYLCHLOROFORMIMINO PHOSPHATES - INTERACTION WITH NEUROPATHY TARGET ESTERASE AND ACETYLCHOLINESTERASE

Acetylcholinesterase (AChE) and neuropathy target esterase (neurotoxic esterase, NTE) are two major target enzymes for organophosphorus (OP) esters. The relative potency of an OP ester to react with AChE or wit h NTE in vitro correlates with its relative potency in vivo to cause a cute toxicity (death) or organopohosphate-induced delayed neurotoxicit y (OPIDN). On this basis extrapolation from in vitro to in vivo data n ow seems justifiable to predict risk of OPIDN. The kinetics of NTE and AChE inhibition by experimental pesticides of the general formula (RO )(2)P(O)ON=CClCH2Cl, where R = methyl, ethyl, isopropyl, propyl, isobu tyl, butyl, pentyl, has been studied. Compounds with short R (methyl, ethyl) were shown to be far more potent inhibitors of AChE than NTE. B oth anti-NTE activity, selectivity for NTE and, correspondingly, the p ropensity of compounds to cause OPIDN rise with increasing their hydro phobicity. A high value of k(i)(NTE)/k(i)(AChE) for R = pentyl suggest s that this compound would have the potential to cause OPIDN at doses lower than the LD50. A quantitative structure-activity relationships ( QSAR) analysis indicated that NTE and AChE have different structural a nd electronic requirements for their respective OP inhibitors. (C) 199 8 Inter Press, Inc.