Synthesis of Photoswitchable Δ9‑Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling

The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabi...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2017-12, Vol.139 (50), p.18206-18212
Main Authors: Westphal, Matthias V, Schafroth, Michael A, Sarott, Roman C, Imhof, Michael A, Bold, Christian P, Leippe, Philipp, Dhopeshwarkar, Amey, Grandner, Jessica M, Katritch, Vsevolod, Mackie, Ken, Trauner, Dirk, Carreira, Erick M, Frank, James A
Format: Article
Language:English
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Summary:The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.7b06456