QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.105221v1 318/2/563    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Astarita, G. Articles by Piomelli, D. Search for Related Content PubMed PubMed Citation Articles by Astarita, G. Articles by Piomelli, D.

BEHAVIORAL PHARMACOLOGY

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

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.)

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- (PPAR-). 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- 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- 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- agonist OEA may provide a scaffold for the discovery of novel orally active PPAR- ligands.

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

This article has been cited by other articles:

				P. Campolongo, B. Roozendaal, V. Trezza, V. Cuomo, G. Astarita, J. Fu, J. L. McGaugh, and D. Piomelli Fat-induced satiety factor oleoylethanolamide enhances memory consolidation PNAS, May 12, 2009; 106(19): 8027 - 8031. [Abstract] [Full Text] [PDF]

				L. M. Lauffer, R. Iakoubov, and P. L. Brubaker GPR119 Is Essential for Oleoylethanolamide-Induced Glucagon-Like Peptide-1 Secretion From the Intestinal Enteroendocrine L-Cell Diabetes, May 1, 2009; 58(5): 1058 - 1066. [Abstract] [Full Text] [PDF]

				M. Scherma, L. V. Panlilio, P. Fadda, L. Fattore, I. Gamaleddin, B. Le Foll, Z. Justinova, E. Mikics, J. Haller, J. Medalie, et al. Inhibition of Anandamide Hydrolysis by Cyclohexyl Carbamic Acid 3'-Carbamoyl-3-yl Ester (URB597) Reverses Abuse-Related Behavioral and Neurochemical Effects of Nicotine in Rats J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 482 - 490. [Abstract] [Full Text] [PDF]

				T. Genovese, E. Esposito, E. Mazzon, R. D. Paola, R. Meli, P. Bramanti, D. Piomelli, A. Calignano, and S. Cuzzocrea Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 12 - 23. [Abstract] [Full Text] [PDF]

				J. Fu, J. Kim, F. Oveisi, G. Astarita, and D. Piomelli Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R45 - R50. [Abstract] [Full Text] [PDF]