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J. Pharmacol. Exp. Ther. 318 (2): 563-570

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.


Pharmacological Characterization of Hydrolysis-Resistant Analogs of Oleoylethanolamide with Potent Anorexiant Properties

Giuseppe Astarita, Barbara Di Giacomo, Silvana Gaetani1, Fariba Oveisi, Timothy R. Compton, Silvia Rivara, Giorgio Tarzia, Marco Mor, and Daniele Piomelli

Department of Pharmacology, University of California, Irvine, California (G.A., S.G., F.O., D.P.); Kadmus Pharmaceuticals, Inc., Irvine, California (T.R.C.); Institute of Medicinal Chemistry, University of Urbino, Urbino, Italy (B.D.G., G.T.); Dipartimento Farmaceutico, University of Parma, Parma, Italy (M.M., S.R.); and Center for Drug Discovery, University of California, Irvine, California (G.A., D.P.)

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.

Received for publication March 24, 2006. Accepted for publication May 12, 2006.

Address correspondence to: Dr. Daniele Piomelli, Department of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625. E-mail: piomelli{at}

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