Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity

Marjolein Soethoudt, Uwe Grether, Jürgen Fingerle, Travis W. Grim, Filomena Fezza, Luciano De Petrocellis, Christoph Ullmer, Benno Rothenhäusler, Camille Perret, Noortje Van Gils, David Finlay, Christa Macdonald, Andrea Chicca, Marianela Dalghi Gens, Jordyn Stuart, Henk De Vries, Nicolina Mastrangelo, Lizi Xia, Georgios Alachouzos, Marc P. Baggelaar & 12 others Andrea Martella, Elliot D. Mock, Hui Deng, Laura H. Heitman, Mark Connor, Vincenzo Di Marzo, Jürg Gertsch, Aron H. Lichtman, Mauro Maccarrone, Pal Pacher*, Michelle Glass, Mario Van Der Stelt

*Corresponding author for this work

Research output: Contribution to journalArticle

111 Citations (Scopus)
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Abstract

The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.

Original languageEnglish
Article number13958
Pages (from-to)1-14
Number of pages14
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 3 Jan 2017

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Receptor pharmacology
  • Target validation

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    Soethoudt, M., Grether, U., Fingerle, J., Grim, T. W., Fezza, F., De Petrocellis, L., ... Van Der Stelt, M. (2017). Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity. Nature Communications, 8, 1-14. [13958]. https://doi.org/10.1038/ncomms13958