Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity
Marjolein Soethoudt1,2, Uwe Grether3, Jürgen Fingerle4
1Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
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.
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