title: Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity.
abstract: N-Acylethanolamines (NAEs) are involved in numerous biological activities in plant and animal systems. The metabolism of these lipids by fatty acid amide hydrolase (FAAH) is a key regulatory point in NAE signaling activity. Several active site-directed inhibitors of FAAH have been identified, but few compounds have been described that enhance FAAH activity. Here we synthesized two sets of phenoxyacyl-ethanolamides from natural products, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, with structural similarity to NAEs and characterized their effects on the hydrolytic activity of FAAH. Both compounds increased the apparent Vmax of recombinant FAAH proteins from both plant (Arabidopsis) and mammalian (Rattus) sources. These NAE-like compounds appeared to act by reducing the negative feedback regulation of FAAH activity by free ethanolamine. Both compounds added to seedlings relieved, in part, the negative growth effects of exogenous NAE12:0. Cardanolethanolamide reduced neuronal viability and exacerbated oxidative stress-mediated cell death in primary cultured neurons at nanomolar concentrations. This was reversed by FAAH inhibitors or exogenous NAE substrate. Collectively, our data suggest that these phenoxyacyl-ethanolamides act to enhance the activity of FAAH and may stimulate the turnover of NAEs in vivo. Hence, these compounds might be useful pharmacological tools for manipulating FAAH-mediated regulation of NAE signaling in plants or animals.
authors.affiliation: From the Center for Plant Lipid Research, Department of Biological Sciences, University of North Texas, Denton, Texas 76203.
authors.forename: Lionel
authors.initials: L
authors.lastname: Faure
authors.forename: Subbiah
authors.initials: S
authors.lastname: Nagarajan
authors.forename: Hyeondo
authors.initials: H
authors.lastname: Hwang
authors.forename: Christa L
authors.initials: CL
authors.lastname: Montgomery
authors.forename: Bibi Rafeiza
authors.initials: BR
authors.lastname: Khan
authors.forename: George
authors.initials: G
authors.lastname: John
authors.forename: Peter
authors.initials: P
authors.lastname: Koulen
authors.forename: Elison B
authors.initials: EB
authors.lastname: Blancaflor
authors.forename: Kent D
authors.initials: KD
authors.lastname: Chapman
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017360:Arabidopsis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis; D007700:Kinetics; D008041:Linoleic Acids / Q000737:chemistry; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010636:Phenols / Q000737:chemistry; D053284:Polyunsaturated Alkamides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D008041:Linoleic Acids; D010636:Phenols; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C038590:cardanol; C109347:linoleoyl ethanolamide; C538777:3-pentadecylphenol
keywords: Arabidopsis; Enzyme Kinetics; Fatty Acid Amide Hydrolase; Lipids; N-Acylethanolamines; Plant; Signaling; Synthetic Compounds