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J Am Chem Soc. 2018 May 16;140(19):6067-6075. doi: 10.1021/jacs.7b11281. Epub 2018 Feb 16.

Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells.

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Laboratorium für Organische Chemie , Eidgenössische Technische Hochschule Zürich , Vladimir-Prelog-Weg 3 , Zürich 8093 , Switzerland.
Department of Rheumatology , Leiden University Medical Center , Albinusdreef 2 , Leiden 2333 ZA , The Netherlands.
Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , Basel 4070 , Switzerland.
Laboratory of Cardiovascular Physiology and Tissue Injury , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane , Rockville , Maryland 20852 , United States.


Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels and receptor occupancy by small molecules are highly desirable. We report the development of LEI121 as a photoreactive probe to study the type 2 cannabinoid receptor (CB2R), a promising GPCR to treat tissue injury and inflammatory diseases. LEI121 is the first CB2R-selective bifunctional probe that covalently captures CB2R upon photoactivation. An incorporated alkyne serves as ligation handle for the introduction of reporter groups. LEI121 enables target engagement studies and visualization of endogenously expressed CB2R in HL-60 as well as primary human immune cells using flow cytometry. Our findings show that strategically functionalized probes allow monitoring of endogenous GPCR expression and engagement in human cells using tandem photoclick chemistry and hold promise as biomarkers in translational drug discovery.

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