Structure-activity relationships for substrates and inhibitors of hen brain neurotoxic esterase

Abstract

(1) Neurotoxic esterase is one of several paraoxon-resistant esterases of hen brain. It has previously been assayed with phenyl phenylacetate as substrate by a differential assay using Mipafox as selective inhibitor. The Mipafox-sensitive activity is a greater proportion (55 per cent) of the total when phenyl valerate is used as substrate and this activity behaves as a single enzyme according to several tests. Phenyl esters of other acids and esters of other phenols are less specific substrates and most are hydrolysed slower than phenyl valerate. (2) Neurotoxic esterase does not significantly hydrolyse peptides or amides but some hydrophobic peptides and amides are non-progr essive inhibitors. (3) Inhibition by a range of organophosphorus, carbamic and sulphur-acid esters has been investigated. (4) Neurotoxic esterase is similar to chymotrypsin and trypsin but unlike acetylcholinesterase in the pattern of inhibition by organophosphorus esters. The structure-activity relationships presented give some guidance for design of non-neurotoxic pesticides. (5) More stable and less toxic alternatives to Mipafox as a selective inhibitor of neurotoxic esterase have been found. (6) Benzenesulphonyl fluoride is a selective inhibitor of some of the Mipafox-resistant esterases. (7) All the esterases were inhibited by PCMB(0.1 mM)and by Zn 2+ (0.4 mM).