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Molecular Pharmacology

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Research ArticleArticle

Quantitative Analysis Reveals Multiple Mechanisms of Allosteric Modulation of the mGlu5 Receptor in Rat Astroglia

Sophie J. Bradley, Christopher J. Langmead, Jeannette M. Watson and R. A. John Challiss
Molecular Pharmacology May 2011, 79 (5) 874-885; DOI: https://doi.org/10.1124/mol.110.068882
Sophie J. Bradley
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Christopher J. Langmead
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Jeannette M. Watson
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R. A. John Challiss
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Abstract

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of the type 5 metabotropic glutamate (mGlu5) receptor have demonstrable therapeutic potential in an array of neurological and psychiatric disorders. Here, we have used rat cortical astrocytes to investigate how PAMs and NAMs mediate their activity and reveal marked differences between PAMs with respect to their modulation of orthosteric agonist affinity and efficacy. Affinity cooperativity factors (α) were assessed using [3H]2-methyl-6-(phenylethynyl)-pyridine (MPEP)-PAM competition binding in the absence and presence of orthosteric agonist, whereas efficacy cooperativity factors (β) were calculated from net affinity/efficacy cooperativity parameters (αβ) obtained from analyses of the abilities of PAMs to potentiate [3H]inositol phosphate accumulation in astrocytes stimulated with a submaximal (EC20) concentration of orthosteric agonist. We report that whereas 3,3′-difluorobenzaldazine (DFB) and 3-cyano-N-(1,3-diphenyl-1H-prazol-5-yl)benzamide (CDPPB) primarily exert their allosteric modulatory effects through modifying the apparent orthosteric agonist affinity at the astrocyte mGlu5 receptor, the effects of S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidinl-1-yl}-methanone (ADX47273) are mediated primarily via efficacy-driven modulation. In [3H]MPEP-NAM competition binding assays, both MPEP and 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP) defined similar specific binding components, with affinities that were unaltered in the presence of orthosteric agonist, indicating wholly negative efficacy-driven modulations. It is noteworthy that whereas M-5MPEP only partially inhibited orthosteric agonist-stimulated [3H]inositol phosphate accumulation in astrocytes, it could completely suppress Ca2+ oscillations stimulated by quisqualate or (S)-3,5-dihydroxyphenylglycine. In contrast, MPEP was fully inhibitory with respect to both functional responses. The finding that M-5MPEP has different functional effects depending on the endpoint measured is discussed as a possible example of permissive allosteric antagonism.

Footnotes

  • This work was supported by a PhD CASE studentship from the Biotechnology and Biological Sciences Research Council of Great Britain (to S.J.B.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.068882.

  • ABBREVIATIONS:

    mGlu
    metabotropic glutamate
    PAM
    positive allosteric modulator
    NAM
    negative allosteric modulator
    MPEP
    2-methyl-6-(phenylethynyl)-pyridine
    5MPEP
    5-methyl-2-(phenylethynyl)pyridine
    M-5MPEP
    2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine
    DHPG
    (S)-3,5-dihydroxyphenylglycine
    ADX47273
    S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidinl-1-yl}-methanone
    DFB
    3, 3′-difluorobenzaldazine
    CDPPB
    3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
    CPPHA
    N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide
    CHO
    Chinese hamster ovary
    [3H]IPx
    [3H]inositol mono, bis-, and trisphosphate fraction.

  • Received September 13, 2010.
  • Accepted February 1, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (5)
Molecular Pharmacology
Vol. 79, Issue 5
1 May 2011
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Research ArticleArticle

Quantitative Analysis Reveals Multiple Mechanisms of Allosteric Modulation of the mGlu5 Receptor in Rat Astroglia

Sophie J. Bradley, Christopher J. Langmead, Jeannette M. Watson and R. A. John Challiss
Molecular Pharmacology May 1, 2011, 79 (5) 874-885; DOI: https://doi.org/10.1124/mol.110.068882

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Research ArticleArticle

Quantitative Analysis Reveals Multiple Mechanisms of Allosteric Modulation of the mGlu5 Receptor in Rat Astroglia

Sophie J. Bradley, Christopher J. Langmead, Jeannette M. Watson and R. A. John Challiss
Molecular Pharmacology May 1, 2011, 79 (5) 874-885; DOI: https://doi.org/10.1124/mol.110.068882
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