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Research ArticleArticle

SIB-1757 and SIB-1893: Selective, Noncompetitive Antagonists of Metabotropic Glutamate Receptor Type 5

Mark A. Varney, Nicholas D. P. Cosford, Christine Jachec, Sara P. Rao, Aida Sacaan, Fen-Fen Lin, Leo Bleicher, Emily M. Santori, Peter J. Flor, Hans Allgeier, Fabrizio Gasparini, Rainer Kuhn, Stephen D. Hess, Gönül Veliçelebi and Edwin C. Johnson
Journal of Pharmacology and Experimental Therapeutics July 1999, 290 (1) 170-181;
Mark A. Varney
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Nicholas D. P. Cosford
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Christine Jachec
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Sara P. Rao
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Aida Sacaan
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Fen-Fen Lin
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Leo Bleicher
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Emily M. Santori
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Peter J. Flor
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Hans Allgeier
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Fabrizio Gasparini
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Rainer Kuhn
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Stephen D. Hess
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Gönül Veliçelebi
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Edwin C. Johnson
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Abstract

Cell lines expressing the human metabotropic glutamate receptor subtype 5a (hmGluR5a) and hmGluR1b were used as targets in an automated high-throughput screening (HTS) system that measures changes in intracellular Ca2+ ([Ca2+]i) using fluorescence detection. This functional screen was used to identify the mGluR5-selective antagonist, SIB-1757 [6-methyl-2-(phenylazo)-3-pyridinol], which inhibited the glutamate-induced [Ca2+]i responses at hmGluR5 with an IC50 of 0.37 μM compared with an IC50 of >100 μM at hmGluR1. Schild analysis demonstrated a noncompetitive mechanism of inhibition. Pharmacophore mapping was used to identify an additional compound, SIB-1893 [(E)-2-methyl-6-(2-phenylethenyl)pyridine], which was also shown to block glutamate-induced increases in [Ca2+]i at hmGluR5 with an IC50of 0.29 μM compared with an IC50 of >100 μM at hmGluR1. SIB-1757 and SIB-1893 showed little or no activity when tested for agonist and antagonist activity at the other recombinant human mGluR subtypes, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and N-methyl-d-aspartate receptors. In rat neonatal brain slices, SIB-1757 and SIB-1893 inhibited (S)-3,5-dihydroxyphenylglycine (DHPG)-evoked inositol phosphate accumulation in hippocampus and striatum by 60% to 80%, with a potency similar to that observed on recombinant mGluR5. However, in the cerebellum, a brain region with low mGluR5 expression, SIB-1757 failed to inhibit DHPG-evoked inositol phosphate accumulation. In cultured rat cortical neurons, SIB-1757 and SIB-1893 largely inhibited DHPG-evoked [Ca2+]i signals, revealing a population of neurons that were less sensitive to SIB-1757 and SIB-1893. This is the first description of highly selective, noncompetitive mGluR5 antagonists. These compounds will be useful tools in evaluating the role of mGluR5 in normal physiology and in animal models of disease.

Footnotes

  • Send reprint requests to: Mark Varney, Ph.D., SIBIA Neurosciences, Inc., 505 Coast Boulevard South, Suite 300, La Jolla, CA 92037. E-mail:mvarney{at}sibia.com

  • Abbreviations:
    mGluR
    metabotropic glutamate receptors
    [Ca2+]i
    intracellular Ca2+
    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    HTS
    high-throughput screening
    DHPG
    (S)-3,5-dihydroxyphenylglycine
    InsP
    inositol phosphate
    hmGluR
    human metabotropic glutamate receptor
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    MCPG
    (S)-α-methyl-4-carboxyphenylglycine
    SIB-1757
    6-methyl-2-(phenylazo)-3-pyridinol
    SIB-1893
    (E)-2-methyl-6-(2-phenylethenyl)pyridine
    • Received January 26, 1999.
    • Accepted March 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 1
1 Jul 1999
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Research ArticleArticle

SIB-1757 and SIB-1893: Selective, Noncompetitive Antagonists of Metabotropic Glutamate Receptor Type 5

Mark A. Varney, Nicholas D. P. Cosford, Christine Jachec, Sara P. Rao, Aida Sacaan, Fen-Fen Lin, Leo Bleicher, Emily M. Santori, Peter J. Flor, Hans Allgeier, Fabrizio Gasparini, Rainer Kuhn, Stephen D. Hess, Gönül Veliçelebi and Edwin C. Johnson
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 170-181;

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Research ArticleArticle

SIB-1757 and SIB-1893: Selective, Noncompetitive Antagonists of Metabotropic Glutamate Receptor Type 5

Mark A. Varney, Nicholas D. P. Cosford, Christine Jachec, Sara P. Rao, Aida Sacaan, Fen-Fen Lin, Leo Bleicher, Emily M. Santori, Peter J. Flor, Hans Allgeier, Fabrizio Gasparini, Rainer Kuhn, Stephen D. Hess, Gönül Veliçelebi and Edwin C. Johnson
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 170-181;
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