Tufail_2026_Cell.Chem.Biol_33_74

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 DAGLalpha/beta 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.