TY - JOUR T1 - Pharmacological Characterization of Hydrolysis-Resistant Analogs of Oleoylethanolamide with Potent Anorexiant Properties JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 563 LP - 570 DO - 10.1124/jpet.106.105221 VL - 318 IS - 2 AU - Giuseppe Astarita AU - Barbara Di Giacomo AU - Silvana Gaetani AU - Fariba Oveisi AU - Timothy R. Compton AU - Silvia Rivara AU - Giorgio Tarzia AU - Marco Mor AU - Daniele Piomelli Y1 - 2006/08/01 UR - http://jpet.aspetjournals.org/content/318/2/563.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -