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Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPAR? 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 (PPAR?), 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?; 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? agonist GW409544. OEA and CC7 interacted with the ligand-binding domain of PPAR? 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 PPAR? and the induction was avoided with PPAR?-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 PPAR? 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 PPAR?, 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?-activating drugs focused on sulfamide derivatives with a long alkyl chain for the treatment of metabolic dysfunction.

SUBMITTER: Moreno-Santos I

PROVIDER: S-EPMC3961330 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.

Moreno-Santos Inmaculada I Pavón Francisco Javier FJ Romero-Cuevas Miguel M Serrano Antonia A Cano Carolina C Suardíaz Margarita M Decara Juan J Suarez Juan J de Fonseca Fernando Rodríguez FR Macías-González Manuel M

PloS one 20140320 3

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 wi ...[more]

PMID: 24651609

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Project description:BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator-activated receptor α) agonist, suppresses coronary stent-induced arterial inflammation and neointimal hyperplasia. METHODS AND RESULTS Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2-4 per animal; 44 stents total). On day 7, intracoronary molecular-structural near-infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent-induced inflammatory protease activity (near-infrared fluorescence target-to-background ratio: pemafibrate, median [25th-75th percentile]: 2.8 [2.5-3.3] versus control, 4.1 [3.3-4.3], P=0.02). At day 28, animals underwent repeat near-infrared fluorescence-optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7-54.1] mm3 versus control, 54.2 [41.2-81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent-induced cellular inflammation and neointima expression of the inflammatory mediators TNF-α (tumor necrosis factor-α) and MMP-9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)-myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.

Dataset Information

Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPAR? agonist structurally related to N-acylethanolamines.

Publications

Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.

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