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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.

Author information

1
†College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
2
‡CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

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.

PMID:
26151231
DOI:
10.1021/acs.jmedchem.5b00227
[Indexed for MEDLINE]

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