Inhibition and aging of neuropathy target esterase by the stereoisomers of a phosphoramidate related to methamidophos

Abstract Discrepancies in the aging reaction between neuropathy target esterase (NTE) inhibited in vitro and in vivo by racemic mixtures of O -alkyl O -2,5-dichlorophenyl phosphoramidates have been observed. It suggested the existence of differences in the interactions (inhibition and aging) between NTE and each stereoisomers of the above mentioned compounds. In order to verify this hypothesis, stereoisomers of O -hexyl O -2,5-dichlorophenyl phosphoramidate (HDCP) were isolated by chiral column chromatography, followed by the evaluation of NTE inhibition and aging for each stereoisomers. The loss of reactivation capacity by KF was used as criterion of aging. The stereoisomer S -(−)-HDCP inhibited hen brain NTE with an I 50 of 7.6 nM for 30 min of incubation, this being similar to the value obtained for the racemic mixture ( I 50 =6.2 nM), and much lower than that recorded for R -(+)-HDCP ( I 50 =191 nM). NTE inhibited by HDCP racemic mixture and the stereoisomer S -(−)-HDCP was reactivated by KF after 20 h of incubation at 37°C. The NTE inhibited by R -(+)-HDCP could not be fully reactivated after inhibition.