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

Award Number: U18DA052537
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: KDA (KNOWLEDGE/DEVELOPMENT/APPLICATION)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	MAKSCIENTIFIC	151 S BEDFORD ST	BURLINGTON	MA	01803	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	1	9/19/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	MAKSCIENTIFIC, LLC	151 S BEDFORD ST STE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Drug Abuse and Addiction Research Programs	000	1	9/13/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $218,855 )
2020	2020	MAKSCIENTIFIC LLC	151 SOUTH BEDFORD SREET, SUITE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Drug Abuse and Addiction Research Programs	001	1	9/21/2020	NEW	$0
2020	2020	MAKSCIENTIFIC LLC	151 SOUTH BEDFORD SREET, SUITE 104-B	BURLINGTON	MA	01803	MIDDLESEX	USA	Drug Abuse and Addiction Research Programs	000	1	9/15/2020	NEW	$218,855
														Subtotal = $218,855

Grand Total All Awards = $218,855

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

Award Number: U18DA052537

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: KDA (KNOWLEDGE/DEVELOPMENT/APPLICATION)

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