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Molecular Pharmacology

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Research ArticleArticle

CPCCOEt, a Noncompetitive Metabotropic Glutamate Receptor 1 Antagonist, Inhibits Receptor Signaling Without Affecting Glutamate Binding

Stephane Litschig, Fabrizio Gasparini, Doris Rueegg, Natacha Stoehr, Peter Josef Flor, Ivo Vranesic, Laurent Prézeau, Jean-Philippe Pin, Christian Thomsen and Rainer Kuhn
Molecular Pharmacology March 1999, 55 (3) 453-461;
Stephane Litschig
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Fabrizio Gasparini
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Doris Rueegg
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Natacha Stoehr
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Peter Josef Flor
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Ivo Vranesic
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Laurent Prézeau
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Jean-Philippe Pin
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Christian Thomsen
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Rainer Kuhn
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Abstract

Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors characterized by a large, extracellular N-terminal domain comprising the glutamate-binding site. In the current study, we examined the pharmacological profile and site of action of the non-amino-acid antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt). CPCCOEt selectively inhibited glutamate-induced increases in intracellular calcium at human mGluR1b (hmGluR1b) with an apparent IC50 of 6.5 μM while having no agonist or antagonist activity at hmGluR2, -4a, -5a, -7b, and -8a up to 100 μM. Schild analysis indicated that CPCCOEt acts in a noncompetitive manner by decreasing the efficacy of glutamate-stimulated phosphoinositide hydrolysis without affecting the EC50 value or Hill coefficient of glutamate. Similarly, CPCCOEt did not displace [3H]glutamate binding to membranes prepared from mGluR1a-expressing cells. To elucidate the site of action, we systematically exchanged segments and single amino acids between hmGluR1b and the related subtype, hmGluR5a. Substitution of Thr815 and Ala818, located at the extracellular surface of transmembrane segment VII, with the homologous amino acids of hmGluR5a eliminated CPCCOEt inhibition of hmGluR1b. In contrast, introduction of Thr815 and Ala818 at the homologous positions of hmGluR5a conferred complete inhibition by CPCCOEt (IC50 = 6.6 μM), i.e., a gain of function. These data suggest that CPCCOEt represents a novel class of G protein-coupled receptor antagonists inhibiting receptor signaling without affecting ligand binding. We propose that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain.

Footnotes

  • Send reprint requests to: Dr. Rainer Kuhn, K-125.6.08, Nervous System, Novartis Pharma AG, CH-4002 Basel, Switzerland. E-mail:Rainer.kuhn{at}pharma.novartis.com

  • Abbreviations:
    (1S
    3R)-ACPD, (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylate
    AIDA
    (RS)-1-aminoindan-1,5-dicarboxylate
    AP4
    l-2-amino-4-phosphonbutyrate
    CPCCOEt
    7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester
    mGluR
    metabotropic glutamate receptor
    GPCR
    G protein-coupled receptor
    TM
    transmembrane
    fura-z/AM
    1-[2-(5-carboxyoxal-2-yl)-6-aminobenzofuran-5-Oxyl]-2-(2′-amino-5′-methylphenoxyethane-N,N,N′,N′-tetraacetic acid)
    PBP
    periplasmic-binding protein
    • Received August 10, 1998.
    • Accepted November 6, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (3)
Molecular Pharmacology
Vol. 55, Issue 3
1 Mar 1999
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Research ArticleArticle

CPCCOEt, a Noncompetitive Metabotropic Glutamate Receptor 1 Antagonist, Inhibits Receptor Signaling Without Affecting Glutamate Binding

Stephane Litschig, Fabrizio Gasparini, Doris Rueegg, Natacha Stoehr, Peter Josef Flor, Ivo Vranesic, Laurent Prézeau, Jean-Philippe Pin, Christian Thomsen and Rainer Kuhn
Molecular Pharmacology March 1, 1999, 55 (3) 453-461;

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Research ArticleArticle

CPCCOEt, a Noncompetitive Metabotropic Glutamate Receptor 1 Antagonist, Inhibits Receptor Signaling Without Affecting Glutamate Binding

Stephane Litschig, Fabrizio Gasparini, Doris Rueegg, Natacha Stoehr, Peter Josef Flor, Ivo Vranesic, Laurent Prézeau, Jean-Philippe Pin, Christian Thomsen and Rainer Kuhn
Molecular Pharmacology March 1, 1999, 55 (3) 453-461;
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