2. Academic Validation
  3. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice

Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice

  • Nat Chem Biol. 2020 Jun;16(6):667-675. doi: 10.1038/s41589-020-0528-7.
Elliot D Mock 1,  Mohammed Mustafa 2,  Ozge Gunduz-Cinar 3,  Resat Cinar 4,  Gavin N Petrie 5,  Vasudev Kantae 1 6,  Xinyu Di 6,  Daisuke Ogasawara 7,  Zoltan V Varga 8,  Janos Paloczi 8,  Cristina Miliano 9,  Giulia Donvito 2,  Annelot C M van Esbroeck 1,  Anouk M F van der Gracht 1,  Ioli Kotsogianni 1,  Joshua K Park 4,  Andrea Martella 1,  Tom van der Wel 1 10,  Marjolein Soethoudt 1,  Ming Jiang 1 10,  Tiemen J Wendel 1,  Antonius P A Janssen 1 10,  Alexander T Bakker 1,  Colleen M Donovan 3,  Laura I Castillo 3,  Bogdan I Florea 11,  Jesse Wat 12,  Helma van den Hurk 12,  Matthias Wittwer 13,  Uwe Grether 13,  Andrew Holmes 3,  Constant A A van Boeckel 1 12,  Thomas Hankemeier 6,  Benjamin F Cravatt 7,  Matthew W Buczynski 9,  Matthew N Hill 5,  Pal Pacher 8,  Aron H Lichtman 2 14,  Mario van der Stelt 15 16
Affiliations

Affiliations

  • 1 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
  • 3 Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), National Institute of Health (NIH), Bethesda, MD, USA.
  • 4 Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA.
  • 5 Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
  • 6 Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
  • 7 Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
  • 8 Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD, USA.
  • 9 School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
  • 10 Oncode Institute, Leiden, the Netherlands.
  • 11 Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
  • 12 Pivot Park Screening Centre B.V., Oss, the Netherlands.
  • 13 Roche Innovation Center Basel, F. Hoffman-La Roche Ltd, Basel, Switzerland.
  • 14 Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
  • 15 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands. m.van.der.stelt@chem.leidenuniv.nl.
  • 16 Oncode Institute, Leiden, the Netherlands. m.van.der.stelt@chem.leidenuniv.nl.
PMID: 32393901 DOI: 10.1038/s41589-020-0528-7
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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