PMID: 8605290Dec 1, 1995Paper

Ethyl octylphosphonofluoridate and analogs: optimized inhibitors of neuropathy target esterase

Chemical Research in Toxicology
S Y Wu, John E Casida

Abstract

The relation between organophosphorus-induced delayed neuropathy (OPIDN) and brain neuropathy target esterase (NTE) inhibition is further examined in hens by structure-activity studies leading to the most potent in vitro NTE inhibitors known, which are then examined for their neuropathic effects in vivo in hens. The principal compounds studied are alkyl alkylphosphonofluoridates and dialkyl phosphorofluoridates. Potencies that exceed those of any previous inhibitors under the standard in vitro NTE assay condition are achieved with alkyl octylphosphonofluoridates (ethyl, isopropyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, and 3-iodopropyl), 2-iodoethyl hexylphosphonofluoridate, and dialkyl phosphorofluoridates [ethyl, nonyl; di(2-iodoethyl); di(3-iodopropyl); dipentyl]. The concentration for 50% NTE inhibition (I50) of these compounds is 0.04-0.14 nM. Thirty-eight less active analogs including aryl phosphonates and aryl phosphates give I50s of 0.27-4730 nM. For highest potency the summation of length of the alkyl and alkoxy groups on phosphorus should be 12-16 atoms (carbons, oxygens, and phosphorus) (a terminal iodo substituent in this relationship is equivalent to a propyl group). In general, the phosphonofluoridates and phos...Continue Reading

Citations

Apr 20, 2004·Toxicology and Applied Pharmacology·Gary B Quistad, John E Casida
Apr 29, 2008·Nature Chemical Biology·Daniel K NomuraJohn E Casida
May 15, 2003·Journal of Toxicology and Environmental Health. Part a·Vladimir V MalyginGalina F Makhaeva
Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Christian D HodnelandMilan Mrksich
Jun 14, 2003·Proceedings of the National Academy of Sciences of the United States of America·Gary B QuistadJohn E Casida
Jan 8, 2014·Journal of Applied Toxicology : JAT·Galina F MakhaevaRudy J Richardson
Mar 1, 1997·Toxicology and Applied Pharmacology·J C RandallR J Richardson
May 15, 2001·Toxicology and Applied Pharmacology·G B QuistadJ E Casida
Jul 25, 2003·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Paul Glynn
Mar 18, 2003·Nature Genetics·Christopher J WinrowCarrolee Barlow
Feb 2, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·Gary B QuistadJohn E Casida

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