# Dual Fatty Acid Amide Hydrolase (FAAH) and Monoacyglycerol Lipase (MAGL) Inhibitors as Novel Agents for Treatment of Cannabis Use Disorder (CUD)

> **NIH NIH U18** · MAKSCIENTIFIC, LLC · 2020 · $218,855

## Abstract

RESEARCH AND OTHER RELATED INFORMATION – Unit 7 – PROJECT SUMMARY
Fatty Acid Amide Hydrolase (FAAH) and Monoacyglycerol lipase (MAGL) as Targets for
Treating Cannabis Use Disorder (CUD)
The widespread use of recreational cannabis has contributed to an alarming increase of cannabis
use disorder (CUD) incidents, especially amongst adolescents, and constitutes a major threat to
public health. There are currently no FDA-approved medications for treating this disorder. CUD
can be attributed to chronic central activation of the cannabinoid (CB1) receptor by Δ9-
tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient of cannabis. The CB1 receptor
is an integral part of the endocannabinoid system and plays a major role in the reward signaling
in response to substances of abuse. Fatty acid amide hydrolase (FAAH) and monoacylglycerol
lipase (MAGL) are the primary hydrolytic enzymes involved in regulating the two major
endocannabinoid, N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonylglycerol
(2-AG) in the brain. FAAH degrades AEA, while MAGL is mostly responsible for the degradation
of 2-AG. In recent studies, we have shown that dual FAAH/MAGL inhibitor AM4302 induces CB1
discriminative stimulus in nonhuman primates. In contrast, in similar experiments FAAH and
MAGL alone had no effect. These striking findings suggest that drugs which simultaneously target
both FAAH and MAGL represent viable therapeutics options to treat cannabis use disorders. Our
approach in this proposal is to develop dual FAAH/MAGL inhibitors as potential treatments for
CUD. We aim to design and synthesize novel inhibitors of our lead compound AM4302 and
optimize its physicochemical and pharmacokinetics properties to obtain druggable candidates. All
new compounds will be evaluated in-vitro fluorescent assays to determine inhibitory activity
against FAAH and MAGL. Potent dual FAAH/MAGL inhibitors will then be tested for CB1 receptor
affinity to exclude compounds that directly activate CB1, to limit potential psychotropic side-
effects. Potent and selective dual FAAH/MAGL inhibitors will be evaluated in pharmacokinetic
studies to assess oral bioavailability and brain permeability. We anticipate identifying 2-3 lead
compounds for evaluation in drug discrimination studies in rats. The discovery of dual
FAAH/MAGL inhibitors will open new opportunities to safe and effective medications for the
treatment of CUD.

## Key facts

- **NIH application ID:** 10107529
- **Project number:** 1U18DA052537-01
- **Recipient organization:** MAKSCIENTIFIC, LLC
- **Principal Investigator:** Shakiru Olajire Alapafuja
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $218,855
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107529

## Citation

> US National Institutes of Health, RePORTER application 10107529, Dual Fatty Acid Amide Hydrolase (FAAH) and Monoacyglycerol Lipase (MAGL) Inhibitors as Novel Agents for Treatment of Cannabis Use Disorder (CUD) (1U18DA052537-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107529. Licensed CC0.

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