title: Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties.
abstract: Oleoylethanolamide (OEA) is an endogenous lipid mediator that reduces food intake, promotes lipolysis, and decreases body weight gain in rodents by activating peroxisome proliferator-activated receptor-alpha (PPAR-alpha). The biological effects of OEA are terminated by two intracellular lipid hydrolase enzymes, fatty-acid amide hydrolase and N-acylethanolamine-hydrolyzing acid amidase. In the present study, we describe OEA analogs that resist enzymatic hydrolysis, activate PPAR-alpha with high potency in vitro, and persistently reduce feeding when administered in vivo either parenterally or orally. The most potent of these compounds, (Z)-(R)-9-octadecenamide,N-(2-hydroxyethyl,1-methyl) (KDS-5104), stimulates transcriptional activity of PPAR-alpha with a half-maximal effective concentration (EC50) of 100 +/- 21 nM (n = 11). Parenteral administration of KDS-5104 in rats produces persistent dose-dependent prolongation of feeding latency and postmeal interval (half-maximal effective dose, ED50 = 2.4 +/- 1.8 mg kg(-1) i.p.; n = 18), as well as increased and protracted tissue exposure compared with OEA. Oral administration of the compound also results in a significant tissue exposure and reduction of food intake in free-feeding rats. These results suggest that the endogenous high-affinity PPAR-alpha agonist OEA may provide a scaffold for the discovery of novel orally active PPAR-alpha ligands.
authors.affiliation: Department of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Giacomo
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaetani
authors.forename: Fariba
authors.initials: F
authors.lastname: Oveisi
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Compton
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D063388:Endocannabinoids; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D009829:Oleic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D001067:Appetite Depressants; D063388:Endocannabinoids; D007202:Indicators and Reagents; C512990:N-(2-hydroxy-1-methylethyl)-9-octadecenamide; D009829:Oleic Acids; D047493:PPAR alpha; D011955:Receptors, Drug; C488250:oleoylethanolamide