Computational and Biological Evaluation of N-octadecyl-N′-propylsulfamide, a Selective PPARα Agonist Structurally Related to N-acylethanolamines

To further understand the pharmacological properties of N-oleoylethanolamine (OEA), a naturally occurring lipid that activates peroxisome proliferator-activated receptor alpha (PPAR alpha), we designed sulfamoyl analogs based on its structure. Among the compounds tested, N-octadecyl-N'-propylsulfamide (CC7) was selected for functional comparison with OEA. The performed studies include the following computational and biological approaches: 1) molecular docking analyses; 2) molecular biology studies with PPAR alpha; 3) pharmacological studies on feeding behavior and visceral analgesia. For the docking studies, we compared OEA and CC7 data with crystallization data obtained with the reference PPAR alpha agonist GW409544. OEA and CC7 interacted with the ligand-binding domain of PPAR alpha in a similar manner to GW409544. Both compounds produced similar transcriptional activation by in vitro assays, including the GST pull-down assay and reporter gene analysis. In addition, CC7 and OEA induced the mRNA expression of CPT1a in HpeG2 cells through PPARa and the induction was avoided with PPAR alpha-specific siRNA. In vivo studies in rats showed that OEA and CC7 had anorectic and antiobesity activity and induced both lipopenia and decreases in hepatic fat content. However, different effects were observed when measuring visceral pain; OEA produced visceral analgesia whereas CC7 showed no effects. These results suggest that OEA activity on the PPARa receptor (e. g., lipid metabolism and feeding behavior) may be dissociated from other actions at alternative targets (e. g., pain) because other non cannabimimetic ligands that interact with PPARa, such as CC7, do not reproduce the full spectrum of the pharmacological activity of OEA. These results provide new opportunities for the development of specific PPAR alpha-activating drugs focused on sulfamide derivatives with a long alkyl chain for the treatment of metabolic dysfunction.