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

Yingpeng Liu; Lipin Ji; Marsha Eno; Shalley Kudalkar; Ai-Ling Li; Marion Schimpgen; Othman Benchama; Paula Morales; Shu Xu; Dow Hurst; Simiao Wu; Khadijah A Mohammad; JodiAnne T Wood; Nikolai Zvonok; Demetris P Papahatjis; Han Zhou; Chandrashekhar Honrao; Ken Mackie; Patricia Reggio; Andrea G Hohmann; Lawrence J Marnett; Alexandros Makriyannis; Spyros P Nikas

doi:10.1021/acs.jmedchem.8b00611

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

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

Authors

Yingpeng Liu¹, Lipin Ji¹, Marsha Eno¹, Shalley Kudalkar², Ai-Ling Li³, Marion Schimpgen⁴, Othman Benchama¹, Paula Morales⁵, Shu Xu², Dow Hurst⁵, Simiao Wu¹, Khadijah A Mohammad¹, JodiAnne T Wood¹, Nikolai Zvonok¹, Demetris P Papahatjis⁴, Han Zhou¹, Chandrashekhar Honrao¹, Ken Mackie³, Patricia Reggio⁵, Andrea G Hohmann³, Lawrence J Marnett², Alexandros Makriyannis^{1

6}, Spyros P Nikas¹

Affiliations

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.

PMID: 30196704
DOI: 10.1021/acs.jmedchem.8b00611

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 ( K_i 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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Amidohydrolases / chemistry
Amidohydrolases / metabolism
Analgesics / chemistry
Analgesics / pharmacology*
Animals
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology*
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism
Enzyme Stability
Freund's Adjuvant / toxicity
HEK293 Cells
Humans
Hyperalgesia / drug therapy*
Hyperalgesia / enzymology
Inflammation / chemically induced
Inflammation / drug therapy*
Inflammation / enzymology
Lectins, C-Type / chemistry
Lectins, C-Type / metabolism
Male
Mice
Mice, Knockout
Monoacylglycerol Lipases / chemistry
Monoacylglycerol Lipases / metabolism
Nociception / drug effects*
Rats
Receptor, Cannabinoid, CB1 / physiology*

Substances

Analgesics
Anti-Inflammatory Agents
Lectins, C-Type
MGL lectin, human
Receptor, Cannabinoid, CB1
Freund's Adjuvant
Cyclooxygenase 2
ABHD6 protein, human
Monoacylglycerol Lipases
Amidohydrolases
fatty-acid amide hydrolase