Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists

Bioorg Med Chem. 2013 Apr 1;21(7):2045-55. doi: 10.1016/j.bmc.2013.01.006. Epub 2013 Jan 16.


Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2.

MeSH terms

  • Catalytic Domain
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / chemistry
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Recombinant Proteins / agonists
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship


  • Pyridones
  • Receptor, Cannabinoid, CB2
  • Recombinant Proteins
  • 2-hydroxypyridine