A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects (Articolo in rivista)

Type

• Articolo in rivista (Classe)
• Prodotto della ricerca (Classe)

Label

• A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects (Articolo in rivista) (literal)

Anno

• 2013-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

• 10.1111/bph.12013 (literal)

Alternative label

• Bisogno Tiziana1; Mahadevan Anu2; Coccurello Roberto3; Chang Jae Won4;Allarà Marco1; Chen Yugang2; Giacovazzo Giacomo3; Lichtman Aron5;Cravatt Benjamin 4; Moles Anna3,6;Di Marzo Vincenzo1 (2013)
  A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects
  in British journal of pharmacology
  (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

• Bisogno Tiziana1; Mahadevan Anu2; Coccurello Roberto3; Chang Jae Won4;Allarà Marco1; Chen Yugang2; Giacovazzo Giacomo3; Lichtman Aron5;Cravatt Benjamin 4; Moles Anna3,6;Di Marzo Vincenzo1 (literal)

Pagina inizio

• 784 (literal)

Pagina fine

• 793 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

• 169 (literal)

Rivista

• British journal of pharmacology (Rivista)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo

• 4 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

• 1Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy; 2Organix Inc., Woburn, MA, USA; 3Cell Biology and Neurobiology Institute, IBCN/IRCCS Fondazione Santa Lucia, Rome, Italy; 4The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA; 5Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA. 6Genomnia srl, Lainate, Milano, Italy. (literal)

Titolo

• A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects (literal)

Abstract

• BACKGROUND.: The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-AG via diacylglycerol lipases (DAGL) ? and ? is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction of endocannabinoid tone, such as hyperphagia in obese subjects. METHODS.: Three new fluorophosphonate compounds: 1-((fluoro(methyl)phosphoryl)oxy)-3-(penthyloxy)propan-2-yl oleate (O-7458); 1-ethoxy-3-((fluoro(methyl)phosphoryl)oxy)propan-2-yl oleate (O-7459); and 1-((fluoro(methyl)phosphoryl)oxy)-3-isopropoxypropan-2-yl oleate (O-7460) were synthesized and characterized in various enzymatic assays. O-7460 was tested on high fat diet intake in mice. RESULTS.: Of the new compounds, O-7460 exhibited the highest potency (IC(50) =690 nM) against the human recombinant DAGL?, and selectivity (IC(50) >10 ?M) towards COS-7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase (FAAH). Competitive activity-based protein profiling confirmed that O-7460 inhibits mouse brain MAGL only at concentrations > 10 ?M, and showed that this compound has only one major \"off-target\", i.e. the serine hydrolase KIAA1363. O-7460 did not exhibit measurable affinity for human recombinant CB(1) or CB(2) cannabinoid receptors (K(i) >10 ?M). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 ?M) reduced 2-AG levels. When administered to mice, O-7460 dose-dependently (0-12 mg/kg, i.p.) inhibited the intake of a high fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight. CONCLUSIONS.: O-7460 might be considered a useful pharmacological tool to investigate further the role played by 2-AG both in vitro and in vivo under physiological as well as pathological conditions. (literal)

Prodotto di

• Istituto di chimica biomolecolare (ICB) (Istituto)
• Struttura, funzione e \"profiling\" di endocannabinoidi e ammidi bioattive di acidi grassi implicati nelle patologie umane (PM.P01.012.001) (Modulo)
• ex SV.P16.003.001 / Modelli animali di deficit neurocomportamentale: meccanismi di adattamento a stress - modelli animali (SV.P16.003.004) (Modulo)

Autore CNR

• TIZIANA BISOGNO (Unità di personale interno)
• ANNA MOLES (Unità di personale interno)
• VINCENZO DI MARZO (Unità di personale interno)
• ROBERTO COCCURELLO (Persona)

Insieme di parole chiave

• Keywords of "A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects" (Insieme di parole chiave)

Incoming links:

Autore CNR di

• TIZIANA BISOGNO (Unità di personale interno)
• ANNA MOLES (Unità di personale interno)
• VINCENZO DI MARZO (Unità di personale interno)
• ROBERTO COCCURELLO (Persona)

Prodotto

• Istituto di chimica biomolecolare (ICB) (Istituto)
• Struttura, funzione e \"profiling\" di endocannabinoidi e ammidi bioattive di acidi grassi implicati nelle patologie umane (PM.P01.012.001) (Modulo)
• ex SV.P16.003.001 / Modelli animali di deficit neurocomportamentale: meccanismi di adattamento a stress - modelli animali (SV.P16.003.004) (Modulo)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#rivistaDi

• British journal of pharmacology (Rivista)

Insieme di parole chiave di

• Keywords of "A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects" (Insieme di parole chiave)