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

Abstract

To further understand the pharmacological properties of N-oleoylethanolamine (OEA), a naturally occurring lipid that activates peroxisome proliferator-activated receptor alpha (PPARα), 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 PPARα; 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 PPARα agonist GW409544. OEA and CC7 interacted with the ligand-binding domain of PPARα 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 PPARα and the induction was avoided with PPARα-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 PPARα 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 PPARα, 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 PPARα-activating drugs focused on sulfamide derivatives with a long alkyl chain for the treatment of metabolic dysfunction.

Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice

“…In the present study, we evaluated the neuroprotective effects of octadecylpropyl sulfamide (SUL), the most potent and stable compound from these new sulfamide derivatives of OEA ( Cano et al, 2007 ), in an adult mouse model of hypoxia-ischemia (HI). SUL was characterized as an effective activator of PPAR-α, with potent hypolipidemic properties, and feeding suppressant effects ( Cano et al, 2007 ; Moreno-Santos et al, 2014 ). Moreover, SUL showed a neuroprotective effect on neuron cultures exposed to the neurotoxin 6-OHDA, reducing the cell death, and increasing the cell viability ( Rodríguez de Fonseca et al, 2012 ).…”

Molecular effect of fenofibrate on PBMC gene transcription related to lipid metabolism in patients with metabolic syndrome

“…After dilution with 900 μl phenol red‐free DMEM, the liposomes were added to the cells. Phenol red‐free DMEM supplemented with 500 μl 15% charcoal‐stripped foetal bovine serum was added 4 h after transfection …”

“…Cell transfection was performed using liposomes containing plasmid DNA which were formed by incubating 1 μg of an expression vector for wild‐type PPARα and RXRα (pSG5), as described, and 1 μg of reporter plasmid CPT1 with 10 μg of N‐[1‐(2,3‐Dioleoyloxy)]‐N,N,N‐trimethylammonium propane (DOTAP) from Roche Applied Science (Basel, Switzerland) for 15 min at room temperature in a total volume of 100 ml. After dilution with 900 μl phenol red‐free DMEM, the liposomes were added to the cells.…”

“…Phenol red-free DMEM supplemented with 500 ll 15% charcoal-stripped foetal bovine serum was added 4 h after transfection. 27 In all cases, the wells were treated for 16 h with solvent (DMSO), with 10 À6 M of a potent and highly selective PPARa agonist (GW7647 by Tocris Bioscience, Bristol, UK) 28 and 10 À4 M of the different specific compounds indicated. The cells were lysed 16 h after onset of stimulation using the lysis buffer (Roche Applied Science, Basel, Switzerland).…”