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

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.

Elliot D. Mock, Mohammed Mustafa, Ozge Gunduz-Cinar, Resat Cinar, Gavin N. Petrie, Vasudev Kantae, Xinyu Di, Daisuke Ogasawara, Zoltan V. Varga, Janos Paloczi, Cristina Miliano, Giulia Donvito, Annelot C. M. van Esbroeck, Anouk M. F. van der Gracht, Ioli Kotsogianni, Joshua K. Park, Andrea Martella, Tom van der Wel, Marjolein Soethoudt, Ming Jiang, Tiemen J. Wendel, Antonius P. A. Janssen, Alexander T. Bakker, Colleen M. Donovan, Laura I. Castillo, Bogdan I. Florea, Jesse Wat, Helma van den Hurk, Matthias Wittwer, Uwe Grether, Andrew Holmes, Constant A. A. van Boeckel, Thomas Hankemeier, Benjamin F. Cravatt, Matthew W. Buczynski, Matthew N. Hill, Pal Pacher, Aron H. Lichtman & Mario van der Stelt | 2020
In: Nature Chemical Biology ; ISSN: 1552-4450
Epub ahead of print DOI: 10.1038/s41589-020-0528-7
Abuse Propensity, Antianxiety Drugs, Anxiety Symptoms, Drug Therapy, Neurobiology, Posttraumatic Stress Disorder, Psychotrauma, PTSD (en)