title: 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.
authors.affiliation: Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03), Instituto de Salud Carlos III, Santiago de Compostela, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Moreno-Santos
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03), Instituto de Salud Carlos III, Santiago de Compostela, Spain; Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero-Cuevas
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03), Instituto de Salud Carlos III, Santiago de Compostela, Spain; Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.affiliation: Grupo Moduladores de Receptores Cannabinoides y PPARs, Instituto de Química Médica, Centro de Química Orgánica "Manuel Lora-Tamayo" del Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cano
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Suardíaz
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03), Instituto de Salud Carlos III, Santiago de Compostela, Spain; Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suarez
authors.affiliation: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03), Instituto de Salud Carlos III, Santiago de Compostela, Spain; Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto IBIMA, Málaga, Spain.
authors.forename: Fernando Rodríguez
authors.initials: FR
authors.lastname: de Fonseca
authors.affiliation: Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03), Instituto de Salud Carlos III, Santiago de Compostela, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Macías-González
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019295:Computational Biology / Q000379:methods*; D003251:Constriction, Pathologic; D004247:DNA / Q000378:metabolism; D004983:Ethanolamines / Q000737:chemistry* / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D008156:Luciferases / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D062105:Molecular Docking Simulation; D047493:PPAR alpha / Q000819:agonists* / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D012996:Solutions; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004983:Ethanolamines; D008024:Ligands; C022203:N-acylethanolamines; C517808:N-octadecyl-N'-propylsulfamide; D047493:PPAR alpha; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D012996:Solutions; D013449:Sulfonamides; D004247:DNA; D008156:Luciferases