title: Comparative studies of O,O-dialkyl-O-chloromethylchloroformimino phosphates: interaction with neuropathy target esterase and acetylcholinesterase.
abstract: 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 with NTE in vitro correlates with its relative potency in vivo to cause acute toxicity (death) or organopohosphate-induced delayed neurotoxicity (OPIDN). On this basis extrapolation from in vitro to in vivo data now seems justifiable to predict risk of OPIDN. The kinetics of NTE and AChE inhibition by experimental pesticides of the general formula (RO)2P(O)ON=CClCH2Cl, where R = methyl, ethyl, isopropyl, propyl, isobutyl, butyl, pentyl, has been studied. Compounds with short R (methyl, ethyl) were shown to be far more potent inhibitors of AChE than NTE. Both anti-NTE activity, selectivity for NTE and, correspondingly, the propensity of compounds to cause OPIDN rise with increasing their hydrophobicity. A high value of ki(NTE)/ki(AChE) for R = pentyl suggests 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 and electronic requirements for their respective OP inhibitors.
authors.affiliation: Laboratory of Pharmacology, Institute of Physiologically Active Substances, Russian Academy of Science, Chernogolovka, Moscow Region.
authors.forename: G F
authors.initials: GF
authors.lastname: Makhaeva
authors.forename: I V
authors.initials: IV
authors.lastname: Filonenko
authors.forename: V L
authors.initials: VL
authors.lastname: Yankovskaya
authors.forename: S B
authors.initials: SB
authors.lastname: Fomicheva
authors.forename: V V
authors.initials: VV
authors.lastname: Malygin
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000465:Algorithms; D000473:Alkanes / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007531:Isoflurophate / Q000031:analogs & derivatives / Q000633:toxicity; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D000473:Alkanes; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D007531:Isoflurophate; C005238:mipafox; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase