Synthesis and Evaluation of Fatty Acid Amides on the N-Oleoylethanolamide-Like Activation of Peroxisome Proliferator Activated Receptor α

A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-alpha downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutarylCoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-alpha agonistic activities. We prepared nine oleic acid amides. Their PPAR-alpha agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1 Delta(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-alpha antagonist, GW6471, inhibited the induction of the PPAR-alpha downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-alpha agonists.