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; 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

doi:10.1038/ncomms13958

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. BaggelaarAndrea 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

Faculty of Medicine, Health and Human Sciences

Research output: Contribution to journal › Article › peer-review

277 Citations (Scopus)

252 Downloads (Pure)

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 language	English
Article number	13958
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms13958
Publication status	Published - 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

Access to Document

10.1038/ncomms13958

Publisher version (open access)Final published version, 985 KBLicence: CC BY

Cite this

Soethoudt, M., Grether, U., Fingerle, J., Grim, T. W., Fezza, F., De Petrocellis, L., Ullmer, C., Rothenhäusler, B., Perret, C., Van Gils, N., Finlay, D., Macdonald, C., Chicca, A., Gens, M. D., Stuart, J., De Vries, H., Mastrangelo, N., Xia, L., Alachouzos, G., ... Van Der Stelt, M. (2017). Cannabinoid CB₂ receptor ligand profiling reveals biased signalling and off-target activity. Nature Communications, 8, 1-14. Article 13958. https://doi.org/10.1038/ncomms13958

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title = "Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity",

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.",

keywords = "Receptor pharmacology, Target validation",

author = "Marjolein Soethoudt and Uwe Grether and J{\"u}rgen Fingerle and Grim, {Travis W.} and Filomena Fezza and {De Petrocellis}, Luciano and Christoph Ullmer and Benno Rothenh{\"a}usler and Camille Perret and {Van Gils}, Noortje and David Finlay and Christa Macdonald and Andrea Chicca and Gens, {Marianela Dalghi} and Jordyn Stuart and {De Vries}, Henk and Nicolina Mastrangelo and Lizi Xia and Georgios Alachouzos and Baggelaar, {Marc P.} and Andrea Martella and Mock, {Elliot D.} and Hui Deng and Heitman, {Laura H.} and Mark Connor and {Di Marzo}, Vincenzo and J{\"u}rg Gertsch and Lichtman, {Aron H.} and Mauro Maccarrone and Pal Pacher and Michelle Glass and {Van Der Stelt}, Mario",

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.",

year = "2017",

month = jan,

day = "3",

doi = "10.1038/ncomms13958",

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Soethoudt, M, Grether, U, Fingerle, J, Grim, TW, Fezza, F, De Petrocellis, L, Ullmer, C, Rothenhäusler, B, Perret, C, Van Gils, N, Finlay, D, Macdonald, C, Chicca, A, Gens, MD, Stuart, J, De Vries, H, Mastrangelo, N, Xia, L, Alachouzos, G, Baggelaar, MP, Martella, A, Mock, ED, Deng, H, Heitman, LH, Connor, M, Di Marzo, V, Gertsch, J, Lichtman, AH, Maccarrone, M, Pacher, P, Glass, M & Van Der Stelt, M 2017, 'Cannabinoid CB₂ receptor ligand profiling reveals biased signalling and off-target activity', Nature Communications, vol. 8, 13958, pp. 1-14. https://doi.org/10.1038/ncomms13958

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T1 - Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity

AU - Soethoudt, Marjolein

AU - Grether, Uwe

AU - Fingerle, Jürgen

AU - Grim, Travis W.

AU - Fezza, Filomena

AU - De Petrocellis, Luciano

AU - Ullmer, Christoph

AU - Rothenhäusler, Benno

AU - Perret, Camille

AU - Van Gils, Noortje

AU - Finlay, David

AU - Macdonald, Christa

AU - Chicca, Andrea

AU - Gens, Marianela Dalghi

AU - Stuart, Jordyn

AU - De Vries, Henk

AU - Mastrangelo, Nicolina

AU - Xia, Lizi

AU - Alachouzos, Georgios

AU - Baggelaar, Marc P.

AU - Martella, Andrea

AU - Mock, Elliot D.

AU - Deng, Hui

AU - Heitman, Laura H.

AU - Connor, Mark

AU - Di Marzo, Vincenzo

AU - Gertsch, Jürg

AU - Lichtman, Aron H.

AU - Maccarrone, Mauro

AU - Pacher, Pal

AU - Glass, Michelle

AU - Van Der Stelt, Mario

N1 - 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.

PY - 2017/1/3

Y1 - 2017/1/3

N2 - 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.

AB - 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.

KW - Receptor pharmacology

KW - Target validation

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