Abstract
The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.
Copyright © 2013. Published by Elsevier Ltd.
MeSH terms
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Administration, Oral
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Animals
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Antipruritics / chemical synthesis*
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Antipruritics / pharmacokinetics
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Antipruritics / pharmacology
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Behavior, Animal / drug effects
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Bridged Bicyclo Compounds / chemical synthesis*
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Bridged Bicyclo Compounds / pharmacokinetics
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Bridged Bicyclo Compounds / pharmacology
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CHO Cells
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Cricetulus
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Disease Models, Animal
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Drug Discovery
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Mice
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Mice, Inbred ICR
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Molecular Docking Simulation
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Pruritus / drug therapy*
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Pruritus / metabolism
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Pruritus / physiopathology
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Pyridones / chemical synthesis*
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Receptor, Cannabinoid, CB1 / chemistry
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Receptor, Cannabinoid, CB2 / agonists*
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Receptor, Cannabinoid, CB2 / chemistry
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Receptor, Cannabinoid, CB2 / metabolism
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Structure-Activity Relationship
Substances
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Antipruritics
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Bridged Bicyclo Compounds
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Pyridones
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2