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Research ArticleArticle

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Yelin Chen, Yi Nong, Cyril Goudet, Kamondanai Hemstapat, Tomas de Paulis, Jean-Philippe Pin and P. Jeffrey Conn
Molecular Pharmacology May 2007, 71 (5) 1389-1398; DOI: https://doi.org/10.1124/mol.106.032425
Yelin Chen
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Yi Nong
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Cyril Goudet
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Kamondanai Hemstapat
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Tomas de Paulis
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Jean-Philippe Pin
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P. Jeffrey Conn
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Abstract

Exciting advances have been made in the discovery of selective positive allosteric modulators of the metabotropic glutamate receptor (mGluR) mGluR5. These compounds may provide a novel approach that could be useful in the treatment of certain central nervous system disorders. However, because of their low potencies, previously described mGluR5 potentiators are not useful for functional studies in native preparations. In addition, binding sites at which these compounds act have not been identified. It has been suggested that two allosteric potentiators, 3,3′-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), act by binding to the same allosteric site as the negative allosteric modulators of mGluR5 such as 2-methyl-6-(phenylethynyl)pyridine (MPEP). However, another mGluR5 potentiator, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)m-ethyl]phenyl}-2-hydroxybenzamide, does not bind to this site, bringing this hypothesis into question. We have synthesized a series of CDPPB analogs and report that these compounds bind to the MPEP site with affinities that are closely related to their potencies as mGluR5 potentiators. Furthermore, allosteric potentiation is antagonized by a neutral ligand at the MPEP site and reduced by a mutation of mGluR5 that eliminates MPEP binding. Together, these data suggest that interaction with the MPEP site is important for allosteric potentiation of mGluR5 by CDPPB and related compounds. In addition, whole-cell patch-clamp studies in midbrain slices reveal that a highly potent analog of CDPPB, 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), selectively potentiates mGluR5 but not mGluR1-mediated responses in midbrain neurons, whereas a previously identified allosteric potentiator of mGluR1 has the opposite effect.

Footnotes

  • This work is supported by grants from the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, the Stanley Foundation, and the National Alliance for Research on Schizophrenia and Affective Disorders. Vanderbilt is a center within the National Institutes of Health-supported Molecular Libraries Screening Centers Network.

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

  • doi:10.1124/mol.106.032425.

  • ABBREVIATIONS: GPCR, G protein-coupled receptor; 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; DFB, 3,3′-difluorobenzaldazine; DMEM, Dulbecco's modified Eagle's medium; DHPG, (S)-3,5-dihydroxyphenylglycine; FBS, fetal bovine serum; HBSS, Hanks' balanced salt solution; 7TM, seven-transmembrane; MPEP, 2-methyl-6-(phenylethynyl)pyridine; methoxyPEPy, 3-methoxy-5-(2-pyridinylethynyl)pyridine; mGluR, metabotropic glutamate receptor; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; 5MPEP, 5-methyl-2-(phenylethynyl)pyridine, VU-29, 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; HEK, human embryonic kidney; IP, inositol phosphate; ACSF, artificial cerebrospinal fluid; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; Ro 67-7476, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine.

    • Received November 7, 2006.
    • Accepted February 13, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (5)
Molecular Pharmacology
Vol. 71, Issue 5
1 May 2007
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Research ArticleArticle

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Yelin Chen, Yi Nong, Cyril Goudet, Kamondanai Hemstapat, Tomas de Paulis, Jean-Philippe Pin and P. Jeffrey Conn
Molecular Pharmacology May 1, 2007, 71 (5) 1389-1398; DOI: https://doi.org/10.1124/mol.106.032425

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Research ArticleArticle

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

Yelin Chen, Yi Nong, Cyril Goudet, Kamondanai Hemstapat, Tomas de Paulis, Jean-Philippe Pin and P. Jeffrey Conn
Molecular Pharmacology May 1, 2007, 71 (5) 1389-1398; DOI: https://doi.org/10.1124/mol.106.032425
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