Cannabinoid CB 2 receptor ligand profiling reveals biased signalling and off-target activity.

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.
Competing Interests: Industry authors U.G., J.F., C.U., B.R. and C.P. are full-time employees of Hoffmann-La Roche and P.P. is full time employee of NIH. All academic authors state that they have no conflict of interest.