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.
Highlights
The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases
Different chemical classes have been described as CBR ligands (for example, mixed CBR agonists: D9-THC, CP55940, WIN55212-2, HU210, and the endogenous ligands 2-arachidonoyl glycerol (2-AG) and anandamide (AEA, N-arachidonoylethanolamine); CB1R antagonists: SR141716A, and AM251; CB2R agonists: HU308, HU910, Gp-1a, JWH015, JWH133 and AM1241; and CB2R antagonists: AM630 and SR144528; see Supplementary Information, Supplementary Fig. 1 for structures)[2,20]
Drug discovery research has focused on the design and synthesis of selective cannabinoid CB2R agonists
Summary
The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. High selectivity and well-defined molecular mode of action of chemical probes are essential to translate the preclinical studies on non-human species to the patient This type of information is, often lacking and reproducibility across different laboratories is sometimes difficult to obtain. CB2R is predominantly expressed on immune cells and its expression level is believed to increase in tissues upon pathological stimuli[2], whereas the CB1R is highly expressed in the brain[16] Both receptors couple to Gi/o proteins and modulate various intracellular signal transduction pathways, such as inhibition of cAMP-production, activation of pERK and G protein-coupled Inward Rectifying K þ -channels (GIRKs) and recruitment of b-arrestin to the receptor[17,18,19]. This whole avenue of research is currently being hampered by possible bias of using non-selective pharmacological, immunological and genetic tools and has delayed the development of novel CB2R-based drugs[22,23]
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