Cannabinoid CB 2 Receptor Ligand Profiling Reveals Biased Signalling and Off-Target Activity

Nat Commun. 2017 Jan 3;8:13958. doi: 10.1038/ncomms13958.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / pharmacology
  • CHO Cells
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoids / pharmacology
  • Cell Line, Tumor
  • Cricetulus
  • Gene Expression
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Kinetics
  • Ligands
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Protein Binding
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Signal Transduction*

Substances

  • Bridged Bicyclo Compounds
  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • HU-910
  • Ligands
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • HU 308
  • 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC