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Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice.
Mock, Elliot D; Mustafa, Mohammed; Gunduz-Cinar, Ozge; Cinar, Resat; Petrie, Gavin N; Kantae, Vasudev; Di, Xinyu; Ogasawara, Daisuke; Varga, Zoltan V; Paloczi, Janos; Miliano, Cristina; Donvito, Giulia; van Esbroeck, Annelot C M; van der Gracht, Anouk M F; Kotsogianni, Ioli; Park, Joshua K; Martella, Andrea; van der Wel, Tom; Soethoudt, Marjolein; Jiang, Ming; Wendel, Tiemen J; Janssen, Antonius P A; Bakker, Alexander T; Donovan, Colleen M; Castillo, Laura I; Florea, Bogdan I; Wat, Jesse; van den Hurk, Helma; Wittwer, Matthias; Grether, Uwe; Holmes, Andrew; van Boeckel, Constant A A; Hankemeier, Thomas; Cravatt, Benjamin F; Buczynski, Matthew W; Hill, Matthew N; Pacher, Pal; Lichtman, Aron H; van der Stelt, Mario.
Afiliación
  • Mock ED; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Mustafa M; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
  • Gunduz-Cinar O; Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), National Institute of Health (NIH), Bethesda, MD, USA.
  • Cinar R; Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA.
  • Petrie GN; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
  • Kantae V; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Di X; Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
  • Ogasawara D; Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
  • Varga ZV; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
  • Paloczi J; Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD, USA.
  • Miliano C; Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD, USA.
  • Donvito G; School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
  • van Esbroeck ACM; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
  • van der Gracht AMF; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Kotsogianni I; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Park JK; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Martella A; Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA.
  • van der Wel T; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Soethoudt M; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Jiang M; Oncode Institute, Leiden, the Netherlands.
  • Wendel TJ; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Janssen APA; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Bakker AT; Oncode Institute, Leiden, the Netherlands.
  • Donovan CM; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Castillo LI; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Florea BI; Oncode Institute, Leiden, the Netherlands.
  • Wat J; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • van den Hurk H; Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), National Institute of Health (NIH), Bethesda, MD, USA.
  • Wittwer M; Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), National Institute of Health (NIH), Bethesda, MD, USA.
  • Grether U; Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Holmes A; Pivot Park Screening Centre B.V., Oss, the Netherlands.
  • van Boeckel CAA; Pivot Park Screening Centre B.V., Oss, the Netherlands.
  • Hankemeier T; Roche Innovation Center Basel, F. Hoffman-La Roche Ltd, Basel, Switzerland.
  • Cravatt BF; Roche Innovation Center Basel, F. Hoffman-La Roche Ltd, Basel, Switzerland.
  • Buczynski MW; Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), National Institute of Health (NIH), Bethesda, MD, USA.
  • Hill MN; Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • Pacher P; Pivot Park Screening Centre B.V., Oss, the Netherlands.
  • Lichtman AH; Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
  • van der Stelt M; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
Nat Chem Biol ; 16(6): 667-675, 2020 06.
Article en En | MEDLINE | ID: mdl-32393901
ABSTRACT
N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fosfatidiletanolaminas / Fosfolipasa D / Conducta Animal / Inhibidores Enzimáticos / Metabolismo de los Lípidos Límite: Animals / Humans / Male Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Países Bajos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fosfatidiletanolaminas / Fosfolipasa D / Conducta Animal / Inhibidores Enzimáticos / Metabolismo de los Lípidos Límite: Animals / Humans / Male Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Países Bajos