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 (PPARα), we designed sulfamoyl analogs based on its structure. Among the compounds tested, N-octadecyl-N'-propylsulfami...

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Autores principales: Inmaculada Moreno-Santos, Francisco Javier Pavón, Miguel Romero-Cuevas, Antonia Serrano, Carolina Cano, Margarita Suardíaz, Juan Decara, Juan Suarez, Fernando Rodríguez de Fonseca, Manuel Macías-González
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Publicado: Public Library of Science (PLoS) 2014
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Acceso en línea:https://doaj.org/article/e8e3c422775b4a99a4cbe5a87e56a9d4
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spelling oai:doaj.org-article:e8e3c422775b4a99a4cbe5a87e56a9d42021-11-18T08:26:58ZComputational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.1932-620310.1371/journal.pone.0092195https://doaj.org/article/e8e3c422775b4a99a4cbe5a87e56a9d42014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24651609/?tool=EBIhttps://doaj.org/toc/1932-6203To 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.Inmaculada Moreno-SantosFrancisco Javier PavónMiguel Romero-CuevasAntonia SerranoCarolina CanoMargarita SuardíazJuan DecaraJuan SuarezFernando Rodríguez de FonsecaManuel Macías-GonzálezPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e92195 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Inmaculada Moreno-Santos
Francisco Javier Pavón
Miguel Romero-Cuevas
Antonia Serrano
Carolina Cano
Margarita Suardíaz
Juan Decara
Juan Suarez
Fernando Rodríguez de Fonseca
Manuel Macías-González
Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.
description 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.
format article
author Inmaculada Moreno-Santos
Francisco Javier Pavón
Miguel Romero-Cuevas
Antonia Serrano
Carolina Cano
Margarita Suardíaz
Juan Decara
Juan Suarez
Fernando Rodríguez de Fonseca
Manuel Macías-González
author_facet Inmaculada Moreno-Santos
Francisco Javier Pavón
Miguel Romero-Cuevas
Antonia Serrano
Carolina Cano
Margarita Suardíaz
Juan Decara
Juan Suarez
Fernando Rodríguez de Fonseca
Manuel Macías-González
author_sort Inmaculada Moreno-Santos
title Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.
title_short Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.
title_full Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.
title_fullStr Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.
title_full_unstemmed Computational and biological evaluation of N-octadecyl-N'-propylsulfamide, a selective PPARα agonist structurally related to N-acylethanolamines.
title_sort computational and biological evaluation of n-octadecyl-n'-propylsulfamide, a selective pparα agonist structurally related to n-acylethanolamines.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/e8e3c422775b4a99a4cbe5a87e56a9d4
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