Scientists created ultra-potent inhibitors of the enzyme that makes the brain's main endocannabinoid, affecting feeding behavior
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Picomolar DAGL inhibition reduced feeding, but off-target effects of the scaffold cloud interpretation
- Evidence Grade:
- Medicinal chemistry study with in vivo validation. Provides important tool compounds but the off-target effects limit conclusions about DAGL-specific biology.
- Study Age:
- Published in 2017. DAGL inhibitor development continues as researchers seek more selective compounds.
- Original Title:
- Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.
- Published In:
- Journal of medicinal chemistry, 60(1), 428-440 (2017)
- Authors:
- Deng, Hui(2), Kooijman, Sander(2), 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
- Database ID:
- RTHC-01367
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
What is DAGL and why does it matter?
DAGL (diacylglycerol lipase) is the enzyme that makes 2-AG, the most abundant endocannabinoid in the brain. 2-AG activates CB1 receptors, the same receptors targeted by THC. Blocking DAGL reduces endocannabinoid production upstream, potentially offering a more subtle way to modulate the cannabinoid system than blocking receptors directly.
Could this lead to appetite-suppressing drugs?
Theoretically, reducing endocannabinoid production could suppress appetite. However, the current compounds have off-target effects, and it remains unknown whether DAGL inhibition would cause the same psychiatric side effects that ended rimonabant's clinical use.
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Cite This Study
https://rethinkthc.com/research/RTHC-01367APA
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
MLA
Deng, Hui, et al. "Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding.." Journal of medicinal chemistry, 2017. https://doi.org/10.1021/acs.jmedchem.6b01482
RethinkTHC
RethinkTHC Research Database. "Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and P..." RTHC-01367. Retrieved from https://rethinkthc.com/research/deng-2017-triazole-ureas-act-as
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.