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

• Published in: Nature communications Vol. 8; no. 1; pp. 13958 - 14
• Main Authors: Soethoudt, Marjolein, Grether, Uwe, Fingerle, Jürgen, Grim, Travis W., Fezza, Filomena, de Petrocellis, Luciano, Ullmer, Christoph, Rothenhäusler, Benno, Perret, Camille, van Gils, Noortje, Finlay, David, MacDonald, Christa, Chicca, Andrea, Gens, Marianela Dalghi, Stuart, Jordyn, de Vries, Henk, Mastrangelo, Nicolina, Xia, Lizi, Alachouzos, Georgios, Baggelaar, Marc P., Martella, Andrea, Mock, Elliot D., Deng, Hui, Heitman, Laura H., Connor, Mark, Di Marzo, Vincenzo, Gertsch, Jürg, Lichtman, Aron H., Maccarrone, Mauro, Pacher, Pal, Glass, Michelle, van der Stelt, Mario
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.01.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/309/436/2387; 631/154/556; 631/92/436/2387; 96; 96/106; 96/109; 96/47; 96/95; Biochemistry; Chemistry; Diabetic neuropathy; Health sciences; Humanities and Social Sciences; Laboratories; Ligands; Medicine; Mode of action; multidisciplinary; Pharmacokinetics; Pharmacology; Physiology; Proteins; Science; Science (multidisciplinary); Signal transduction; Tetrahydrocannabinol; THC; Italy; Netherlands; United States > US; Switzerland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13958

The cannabinoid CB 2 receptor (CB 2 R) 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 CB 2 R, 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 CB 2 R 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 CB 2 R agonists to study the role of CB 2 R 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. CB 2 receptor agonists are developed as potential analgesics or immune-modulatory compounds. Here, the authors characterize the pharmacological properties of widely used CB 2 receptor agonists and antagonists, recommending three that appear most suitable for in vitro and in vivo studies.