2. Academic Validation
  3. Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism

Suppression of pain transmission and behavior by inhibition of peripheral diacylglycerol metabolism

  • Cell Chem Biol. 2026 Jan 15;33(1):74-90.e19. doi: 10.1016/j.chembiol.2025.12.008.
Yusuf Z Tufail 1,  Carlos Guijas 1,  David A Kummer 1,  Cassandra L Henry 2,  Jeanne V Moody 2,  Taylor Andalis 2,  Bryan Boyd 2,  Jacob Gil 1,  Jacquelyn Ha 2,  Dylan M Herbst 2,  Rachel A Herbst-Graham 2,  Clayton Hutton 2,  Ellen M Kozina 1,  Micah J Niphakis 2,  Nhi Ngo 2,  Gary P O'Neill 2,  Holly T Reardon 2,  Michael Shaghafi 1,  Olesya A Ulanovskaya 2,  Nicholas Raffaele 2,  Andreu Viader 1,  Olivia D Weber 1,  Todd K Jones 1,  Cheryl A Grice 2,  John J M Wiener 2,  Klaus B Simonsen 1,  Jacqueline L Blankman 2,  Jason R Clapper 3
Affiliations

Affiliations

  • 1 Lundbeck La Jolla Research Center, 10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA.
  • 2 Lundbeck La Jolla Research Center, 10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA; Abide Therapeutics, 10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA.
  • 3 Lundbeck La Jolla Research Center, 10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA; Abide Therapeutics, 10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA. Electronic address: [email protected].
PMID: 41544618 DOI: 10.1016/j.chembiol.2025.12.008
Abstract

Diacylglycerol Lipase (DAGL) produces 2-arachidonoylglycerol (2-AG) and Other proinflammatory lipids. Inactivation of DAGLs reduces the production of 2-AG, arachidonic acid (AA) and eicosanoids and elicits antinociceptive and anti-(neuro)inflammatory effects in rodents. However, inhibitors that enter the brain can cause significant central nervous system (CNS) side effects. Using activity-based protein profiling (ABPP), we report the discovery of A1480LS, a potent, in vivo active, small molecule dual inhibitor of DAGLα/β that is functionally biased to the periphery. We demonstrate that A1480LS reduces pain behaviors and nociceptor activity in animal models. Moreover, A1480LS accomplishes this by reducing 2-AG and Other lipids in peripheral tissues without causing adverse CNS effects. Overall, we show that inhibiting DAG metabolism in the periphery elicits antinociceptive effects that can be functionally dissected from adverse central effects and provide preclinical validation for a non-narcotic strategy to treat pain.

Keywords

2-arachidonoylglycerol; activity-based protein profiling; analgesia; arachidonic acid; diacylglycerol lipase; eicosanoid; inhibitor; neuropathic pain; peripheral; prostaglandin.

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