Abstract
SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
MeSH terms
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Aza Compounds / chemical synthesis*
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Calcium / metabolism
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Cell Line
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Cerebellum / metabolism
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Fluorenes / chemical synthesis*
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Fluorenes / chemistry
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Fluorenes / pharmacology
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Male
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Pain Measurement
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Receptors, Metabotropic Glutamate / genetics
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Receptors, Metabotropic Glutamate / metabolism
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Structure-Activity Relationship
Substances
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9-dimethylamino-3-(4-ethylphenyl)-3H-5-thia-1,3,6-triazafluoren-4-one
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Analgesics
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Aza Compounds
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Fluorenes
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Heterocyclic Compounds, 3-Ring
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor type 1
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Calcium