title: Cannabinoid CB2receptor ligand profiling reveals biased signalling and off-target activity.
abstract: The cannabinoid CB2receptor (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.
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.|Department of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Soethoudt
authors.affiliation: Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., Grenzachterstrasse 124, Basel 4070, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Grether
authors.affiliation: Department of Biochemistry, NMI, University Tübingen, Markwiesenstrasse 55, Reutlingen 72770, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fingerle
authors.affiliation: Department of Pharmacology and Toxicology, 1220 East Broad Street, PO Box 980613, Richmond, Virginia 23298-0613, USA.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Grim
authors.affiliation: Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, Rome 00133, Italy.|European Center for Brain Research/IRCCS Santa Lucia Foundation, via del Fosso del Fiorano 65, Rome 00143, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Fezza
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Via Campi Flegrei 34, Comprensorio Olivetti, Pozzuoli 80078, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: de Petrocellis
authors.affiliation: Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., Grenzachterstrasse 124, Basel 4070, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ullmer
authors.affiliation: Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., Grenzachterstrasse 124, Basel 4070, Switzerland.
authors.forename: Benno
authors.initials: B
authors.lastname: Rothenhäusler
authors.affiliation: Roche Innovation Center Basel, F. Hoffman-La Roche Ltd., Grenzachterstrasse 124, Basel 4070, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Perret
authors.affiliation: Department of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Noortje
authors.initials: N
authors.lastname: van Gils
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park road, Grafton, Auckland 1023, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: Finlay
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park road, Grafton, Auckland 1023, New Zealand.
authors.forename: Christa
authors.initials: C
authors.lastname: MacDonald
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, Bern CH-3012, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chicca
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, Bern CH-3012, Switzerland.
authors.forename: Marianela Dalghi
authors.initials: MD
authors.lastname: Gens
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, New South Wales 2109, Australia.
authors.forename: Jordyn
authors.initials: J
authors.lastname: Stuart
authors.affiliation: Department of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.affiliation: Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, Rome 00128, Italy.
authors.forename: Nicolina
authors.initials: N
authors.lastname: Mastrangelo
authors.affiliation: Department of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Lizi
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Georgios
authors.initials: G
authors.lastname: Alachouzos
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Baggelaar
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.|Department of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martella
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Elliot D
authors.initials: ED
authors.lastname: Mock
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, New South Wales 2109, Australia.
authors.forename: Mark
authors.identifier: 0000-0003-2538-2001
authors.initials: M
authors.lastname: Connor
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Via Campi Flegrei 34, Comprensorio Olivetti, Pozzuoli 80078, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, Bern CH-3012, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.affiliation: Department of Pharmacology and Toxicology, 1220 East Broad Street, PO Box 980613, Richmond, Virginia 23298-0613, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: European Center for Brain Research/IRCCS Santa Lucia Foundation, via del Fosso del Fiorano 65, Rome 00143, Italy.|Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, Rome 00128, Italy.
authors.forename: Mauro
authors.identifier: 0000-0002-3990-2963
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/NIAAA, 5625 Fishers Lane, Rockville, Maryland 20852, USA.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park road, Grafton, Auckland 1023, New Zealand.
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
authors.affiliation: Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D045744:Cell Line, Tumor; D003412:Cricetulus; D015870:Gene Expression; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001643:Bridged Bicyclo Compounds; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; C573862:HU-910; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C402416:HU 308; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC