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

Author

Listed:
  • Marjolein Soethoudt

    (Leiden Institute of Chemistry, Leiden University
    Leiden Academic Centre for Drug Research, Leiden University)

  • Uwe Grether

    (Roche Innovation Center Basel, F. Hoffman-La Roche Ltd.)

  • Jürgen Fingerle

    (NMI, University Tübingen)

  • Travis W. Grim

    (Department of Pharmacology and Toxicology)

  • Filomena Fezza

    (Tor Vergata University of Rome
    European Center for Brain Research/IRCCS Santa Lucia Foundation)

  • Luciano de Petrocellis

    (Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R.)

  • Christoph Ullmer

    (Roche Innovation Center Basel, F. Hoffman-La Roche Ltd.)

  • Benno Rothenhäusler

    (Roche Innovation Center Basel, F. Hoffman-La Roche Ltd.)

  • Camille Perret

    (Roche Innovation Center Basel, F. Hoffman-La Roche Ltd.)

  • Noortje van Gils

    (Leiden Academic Centre for Drug Research, Leiden University)

  • David Finlay

    (Faculty of Medical and Health Sciences, University of Auckland)

  • Christa MacDonald

    (Faculty of Medical and Health Sciences, University of Auckland)

  • Andrea Chicca

    (Institute of Biochemistry and Molecular Medicine, University of Bern)

  • Marianela Dalghi Gens

    (Institute of Biochemistry and Molecular Medicine, University of Bern)

  • Jordyn Stuart

    (Faculty of Medicine and Health Sciences, Macquarie University, North Ryde)

  • Henk de Vries

    (Leiden Academic Centre for Drug Research, Leiden University)

  • Nicolina Mastrangelo

    (Campus Bio-Medico University of Rome)

  • Lizi Xia

    (Leiden Academic Centre for Drug Research, Leiden University)

  • Georgios Alachouzos

    (Leiden Institute of Chemistry, Leiden University)

  • Marc P. Baggelaar

    (Leiden Institute of Chemistry, Leiden University)

  • Andrea Martella

    (Leiden Institute of Chemistry, Leiden University
    Leiden Academic Centre for Drug Research, Leiden University)

  • Elliot D. Mock

    (Leiden Institute of Chemistry, Leiden University)

  • Hui Deng

    (Leiden Institute of Chemistry, Leiden University)

  • Laura H. Heitman

    (Leiden Academic Centre for Drug Research, Leiden University)

  • Mark Connor

    (Faculty of Medicine and Health Sciences, Macquarie University, North Ryde)

  • Vincenzo Di Marzo

    (Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R.)

  • Jürg Gertsch

    (Institute of Biochemistry and Molecular Medicine, University of Bern)

  • Aron H. Lichtman

    (Department of Pharmacology and Toxicology)

  • Mauro Maccarrone

    (European Center for Brain Research/IRCCS Santa Lucia Foundation
    Campus Bio-Medico University of Rome)

  • Pal Pacher

    (Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/NIAAA)

  • Michelle Glass

    (Faculty of Medical and Health Sciences, University of Auckland)

  • Mario van der Stelt

    (Leiden Institute of Chemistry, Leiden University)

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.

Suggested Citation

  • Marjolein Soethoudt & Uwe Grether & Jürgen Fingerle & Travis W. Grim & Filomena Fezza & Luciano de Petrocellis & Christoph Ullmer & Benno Rothenhäusler & Camille Perret & Noortje van Gils & David Finl, 2017. "Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13958
    DOI: 10.1038/ncomms13958
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    Cited by:

    1. Xiaoting Li & Hao Chang & Jara Bouma & Laura V. Paus & Partha Mukhopadhyay & Janos Paloczi & Mohammed Mustafa & Cas Horst & Sanjay Sunil Kumar & Lijie Wu & Yanan Yu & Richard J. B. H. N. Berg & Antoni, 2023. "Structural basis of selective cannabinoid CB2 receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Karel Miettinen & Nattawat Leelahakorn & Aldo Almeida & Yong Zhao & Lukas R. Hansen & Iben E. Nikolajsen & Jens B. Andersen & Michael Givskov & Dan Staerk & Søren Bak & Sotirios C. Kampranis, 2022. "A GPCR-based yeast biosensor for biomedical, biotechnological, and point-of-use cannabinoid determination," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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