Abstract
In our search for new cannabinoid receptor modulators, we describe herein the design and synthesis of three sets of indole-based ligands characterized by an acetamide, oxalylamide, or carboxamide chain, respectively. Most of the compounds showed affinity for CB2 receptors in the nanomolar range, with K(i) values spanning 3 orders of magnitude (377-0.37 nM), and moderate to good selectivity over CB1 receptors. Their in vitro functional activity as inverse agonists was confirmed in vivo in the formalin test of acute peripheral and inflammatory pain in mice, in which compounds 10a and 11e proved to be able to reverse the effect of the CB2 selective agonist COR167.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Animals
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CHO Cells
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Combinatorial Chemistry Techniques
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Cricetinae
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Cricetulus
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Cyclic AMP / biosynthesis
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Drug Design
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Drug Inverse Agonism
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HEK293 Cells
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Humans
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Immunologic Factors / chemical synthesis
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Immunologic Factors / chemistry
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Immunologic Factors / pharmacology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Inflammation / drug therapy
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Mice
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Models, Molecular
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Pain / drug therapy
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Pain / immunology
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Pain Measurement
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Radioligand Assay
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Receptor, Cannabinoid, CB2 / agonists
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Receptor, Cannabinoid, CB2 / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Amides
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Immunologic Factors
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Indoles
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Receptor, Cannabinoid, CB2
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Cyclic AMP