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J Med Chem. 2018 Oct 11;61(19):8639-8657. doi: 10.1021/acs.jmedchem.8b00611. Epub 2018 Sep 21.

( R)- N-(1-Methyl-2-hydroxyethyl)-13-( S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes.

Author information

1
Center for Drug Discovery and Department of Pharmaceutical Sciences , Northeastern University , Boston , Massachusetts 02115 , United States.
2
Departments of Biochemistry, Chemistry, and Pharmacology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.
3
Department of Biological and Brain Sciences , Indiana University , Bloomington , Indiana 47405 , United States.
4
Institute of Organic and Pharmaceutical Chemistry , National Hellenic Research Foundation , 48 Vass. Constantinou , Athens 116-35 , Greece.
5
Center for Drug Discovery, Department of Chemistry and Biochemistry , University of North Carolina at Greensboro , Greensboro , North Carolina 27402 , United States.
6
Departments of Chemistry and Chemical Biology , Northeastern University , Boston , Massachusetts 02115 , United States.

Abstract

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( Ki of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 ± 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.

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