Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties.
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.
Astarita
Giuseppe
G
Department of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625, USA.
Di Giacomo
Barbara
B
Gaetani
Silvana
S
Oveisi
Fariba
F
Compton
Timothy R
TR
Rivara
Silvia
S
Tarzia
Giorgio
G
Mor
Marco
M
Piomelli
Daniele
D
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
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