Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system

Eur J Med Chem. 2018 Jun 25;154:155-171. doi: 10.1016/j.ejmech.2018.05.019. Epub 2018 May 14.


The endocannabinoid system (ECS) represents one of the major neuromodulatory systems involved in different physiological and pathological processes. Multi-target compounds exert their activities by acting via multiple mechanisms of action and represent a promising pharmacological modulation of the ECS. In this work we report 4-substituted and 4,5-disubstituted 1,2-dihydro-2-oxo-pyridine-3-carboxamide derivatives with a broad spectrum of affinity and functional activity towards both cannabinoid receptors and additional effects on the main components of the ECS. In particular compound B3 showed high affinity for CB1R (Ki = 23.1 nM, partial agonist) and CB2R (Ki = 6.9 nM, inverse agonist) and also significant inhibitory activity (IC50 = 70 nM) on FAAH with moderate inhibition of ABHD12 (IC50 = 2.5 μΜ). Compounds B4, B5 and B6 that act as full agonists at CB1R and as partial agonists (B5 and B6) or antagonist (B4) at CB2R, exhibited an additional multi-target property by inhibiting anandamide uptake with sub-micromolar IC50 values (0.28-0.62 μΜ). The best derivatives showed cytotoxic activity on U937 lymphoblastoid cells. Finally, molecular docking analysis carried out on the three-dimensional structures of CB1R and CB2R and of FAAH allowed to rationalize the structure-activity relationships of this series of compounds.

Keywords: Cannabinoid receptors; Endocannabinoid system; Molecular docking; Polypharmacology; U251MG glioblastoma cell line; U937 lymphoblastoid cells.

MeSH terms

  • Dose-Response Relationship, Drug
  • Endocannabinoids / chemical synthesis
  • Endocannabinoids / chemistry
  • Endocannabinoids / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, Cannabinoid / metabolism*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • U937 Cells


  • Endocannabinoids
  • Pyridines
  • Receptors, Cannabinoid