title: Development of Quinoline-2,4(1H,3H)-diones as Potent and Selective Ligands of the Cannabinoid Type 2 Receptor.
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.
authors.affiliation: †College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Han
authors.affiliation: ‡CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Zhang
authors.affiliation: †College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qian
authors.affiliation: †College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chen
authors.affiliation: †College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Jian-Bin
authors.initials: JB
authors.lastname: Pu
authors.affiliation: ‡CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.affiliation: †College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D005260:Female; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D009103:Multiple Sclerosis / Q000188:drug therapy; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*
chemical_list: D008024:Ligands; D011804:Quinolines; D043885:Receptor, Cannabinoid, CB2