Abstract
To obtain information on the pharmacophoric requirements of the CB1/CB2 partial agonist BAY 59-3074 we have synthesized a series of new conformationally constrained dibenzofuran (4a-d) and dibenzopyran analogs (5). All constrained analogs exhibited reduced binding affinity at both cannabinoid receptor subtypes, suggesting that planar conformations of these ligands are less favored by both receptors. We also found that 4c, 4d, and 5 exhibited 3- to 12-fold selectivity for hCB2 over rCB1 receptors and may serve as new chemotypes for the development of CB2-selective cannabinergics.
Copyright © 2011. Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alkanesulfonates / chemistry
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Alkanesulfonates / metabolism*
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Alkanesulfonates / pharmacology
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / metabolism*
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Analgesics / pharmacology
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Animals
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Benzofurans / chemical synthesis
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Benzofurans / chemistry
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Benzofurans / metabolism*
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Benzofurans / pharmacology
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Benzopyrans / chemical synthesis
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Benzopyrans / chemistry
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Benzopyrans / metabolism*
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Benzopyrans / pharmacology
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Chronic Pain / drug therapy
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Chronic Pain / physiopathology
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Computer Simulation
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Drug Design*
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Drug Evaluation, Preclinical
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Humans
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Ligands
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Mice
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Molecular Conformation
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Molecular Targeted Therapy
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Neuralgia / drug therapy
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Neuralgia / physiopathology
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Nitriles / chemistry
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Nitriles / metabolism*
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Nitriles / pharmacology
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Protein Binding
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Radioligand Assay
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Receptor, Cannabinoid, CB1 / agonists
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Receptor, Cannabinoid, CB1 / metabolism*
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Receptor, Cannabinoid, CB2 / agonists
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Receptor, Cannabinoid, CB2 / metabolism*
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Software
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Structure-Activity Relationship
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Substrate Specificity
Substances
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3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluoro-1-butanesulfonate
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Alkanesulfonates
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Analgesics
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Benzofurans
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Benzopyrans
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Ligands
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Nitriles
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2