Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists

Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and o...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-04, Vol.21 (7), p.2045-2055
Main Authors: Kusakabe, Ken-ichi, Tada, Yukio, Iso, Yasuyoshi, Sakagami, Masahiro, Morioka, Yasuhide, Chomei, Nobuo, Shinonome, Satomi, Kawamoto, Keiko, Takenaka, Hideyuki, Yasui, Kiyoshi, Hamana, Hiroshi, Hanasaki, Kohji
Format: Article
Language:English
Subjects:
adverse effects
Agonist
agonists
Cannabinoid
Cannabinoid CB2 receptors
Carbon
Catalytic Domain
CB2
chemistry
Drug Design
Homology
Homology model
Humans
Lipophilic
Molecular Docking Simulation
Pain
Physicochemical properties
prediction
Pyridine-2-one
Pyridone
Pyridones - chemical synthesis
Pyridones - chemistry
Pyridones - pharmacology
Receptor, Cannabinoid, CB2 - agonists
Receptor, Cannabinoid, CB2 - chemistry
Receptor, Cannabinoid, CB2 - metabolism
Recombinant Proteins - agonists
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
scaffolds
screening
Side effects
Structure-Activity Relationship
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Description
Summary:Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.01.006