Researchers developed picomolar-potency inhibitors of DAGL (the enzyme that produces 2-AG, the brain's most abundant endocannabinoid), and found they temporarily reduced food intake in fasting mice, similar to CB1 receptor blockers.
Read this if you're interested in targeting endocannabinoid production rather than receptors to control appetite.
Picomolar DAGL inhibition reduced feeding, but off-target effects of the scaffold cloud interpretation
What the researchers found
Through systematic medicinal chemistry, researchers created DH376 (compound 38), an inhibitor of diacylglycerol lipase (DAGL) with picomolar (trillionths of a molar) potency. DAGL is the enzyme responsible for producing 2-AG, the most abundant endocannabinoid that activates CB1 receptors.
In mice, DH376 temporarily reduced feeding after fasting, mimicking the effect of CB1 receptor inverse agonists. However, a negative control compound (DO53) that does not inhibit DAGL also affected feeding, suggesting these triazole urea compounds may influence energy balance through multiple molecular targets, not just DAGL inhibition.
Why it matters
Rather than blocking CB1 receptors directly (as rimonabant did), this approach targets the upstream enzyme that produces the endocannabinoid that activates CB1. However, the finding that non-DAGL-targeting compounds also affected feeding complicates the picture and suggests these chemical tools need further refinement.
The numbers in context
DH376: picomolar DAGL inhibition. Temporarily reduced fasting-induced refeeding in mice. Negative control DO53 (non-DAGL inhibitor) also affected feeding, indicating off-target effects of the triazole urea scaffold.
How the study worked
Structure-activity relationship studies with enantio- and diastereoselective synthesis of triazole urea compounds. In vitro: potency testing against DAGL and other serine hydrolases. In vivo: fasting-refeeding assay in mice comparing active DAGL inhibitors with a negative control compound.
What this study cannot tell us
The negative control compound also affected feeding, undermining the conclusion that the feeding effects are DAGL-specific. These are tool compounds, not drug candidates. The triazole urea scaffold affects multiple serine hydrolases. Only acute feeding effects were tested.
How to read the evidence
Medicinal chemistry study with in vivo validation. Provides important tool compounds but the off-target effects limit conclusions about DAGL-specific biology.
When this study was published
Published in 2017. DAGL inhibitor development continues as researchers seek more selective compounds.
The bigger picture
Reducing endocannabinoid production rather than blocking receptors represents an upstream approach to modulating the cannabinoid system. If DAGL inhibitors can be made truly selective, they could offer a more physiological way to reduce endocannabinoid tone, potentially with fewer side effects than direct receptor blockade.
Questions still open
- Can truly selective DAGL inhibitors be developed without off-target serine hydrolase effects? Would chronic DAGL inhibition produce the psychiatric side effects seen with CB1 blockers? Does reducing 2-AG production have different downstream effects than blocking CB1 directly?
Common questions
What is DAGL and why does it matter?
Could this lead to appetite-suppressing drugs?
Read the original research
Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.
Journal of medicinal chemistry, 60(1), 428-440
Citation
Deng, Hui; Kooijman, Sander; van den Nieuwendijk, Adrianus M C H; Ogasawara, Daisuke; van der Wel, Tom; van Dalen, Floris; Baggelaar, Marc P; Janssen, Freek J; van den Berg, Richard J B H N; den Dulk, Hans; Cravatt, Benjamin F; Overkleeft, Herman S; Rensen, Patrick C N; van der Stelt, Mario. (2017). Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.. Journal of medicinal chemistry, 60(1), 428-440. https://doi.org/10.1021/acs.jmedchem.6b01482
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