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.)
- Address correspondence to:
Dr. Daniele Piomelli, Department of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625. E-mail: piomelli{at}uci.edu
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-α (PPAR-α). 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-α 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-α 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-α agonist OEA may provide a scaffold for the discovery of novel orally active PPAR-α ligands.
Footnotes
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This work was supported by National Institutes of Health Grant DK070347 (to D.P.), Kadmus Pharmaceuticals, Italian MIUR, University of Urbino (to B.D.G. and G.T.), and University of Parma (S.P. and M.M.). The contribution of the Agilent Technologies/University of California, Irvine Analytical Discovery Facility, Center for Drug Discovery is gratefully acknowledged.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.105221.
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ABBREVIATIONS: OEA, oleoylethanolamide; PPAR, peroxisome proliferator-activated receptor; LBD, ligand-binding domain; GW7647, propanoic acid, 2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methyl; Wy-14643, acetic acid, [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]; MD, molecular dynamics; AUC, area under the curve; FAAH, fatty-acid amide hydrolase; URB597, carbamic acid, cyclohexyl-, 3′-(aminocarbonyl)[1,1′-biphenyl]-3-yl ester; EtOAc, ethyl acetate; KDS-5104, (Z)-(R)-9-octadecenamide,N-(2-hydroxyethyl,1-methyl); LC, liquid chromatography; MS, mass spectrometry; EI, electron ionization; GW409544, l-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl]; PMI, postmeal interval; IR, infrared.
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↵1 Current affiliation: Department of Pharmacology and Human Physiology, University of Rome “La Sapienza,” Rome, Italy.
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- Received March 24, 2006.
- Accepted May 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
