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J Med Chem. 2015 Aug 13;58(15):5751-69. doi: 10.1021/acs.jmedchem.5b00227. Epub 2015 Jul 23.

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

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†College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
‡CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.


The cannabinoid type 2 receptors (CB2Rs) play crucial roles in inflammatory diseases. There has been considerable interest in developing potent and selective ligands 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.

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