Development of Quinoline-2,4(1H,3H)-diones as Potent and Selective ligands of the Cannabinoid Type 2 Receptor.

The cannabinoid type 2 receptor (CB2R) plays crucial roles in inflammatory diseases. There has been considerable interest in developing potent and selective ligand for CB2R. In this study, quinoline-2,4(1H,3H)-dione analogs have been designed, synthesized, and evaluated for their potencies and binding properties toward the cannabinoid type 1 receptor (CB1R) and CB2R. C5- or C8- substituted quinoline-2,4(1H,3H)-diones demonstrate CB2R agonist activity, while the C6- or C7- substituted analogs are antagonists of CB2R. In addition, oral administration of 21 dose-dependently alleviates the clinical symptoms of experimental autoimmune encephalomyelitis in a mouse model of Multiple Sclerosis, and protects the central nervous system from immune damage. Furthermore, the interaction modes predicted by docking simulations and the 3D-QSAR model generated with CoMFA may offer guidance for further design and modification of CB2R modulators.