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Research ArticleArticle

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Alice L. Rodriguez, Mark D. Grier, Carrie K. Jones, Elizabeth J. Herman, Alexander S. Kane, Randy L. Smith, Richard Williams, Ya Zhou, Joy E. Marlo, Emily L. Days, Tasha N. Blatt, Satyawan Jadhav, Usha N. Menon, Paige N. Vinson, Jerri M. Rook, Shaun R. Stauffer, Colleen M. Niswender, Craig W. Lindsley, C. David Weaver and P. Jeffrey Conn
Molecular Pharmacology December 2010, 78 (6) 1105-1123; DOI: https://doi.org/10.1124/mol.110.067207
Alice L. Rodriguez
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Mark D. Grier
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Carrie K. Jones
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Elizabeth J. Herman
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Alexander S. Kane
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Randy L. Smith
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Richard Williams
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Ya Zhou
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Joy E. Marlo
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Emily L. Days
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Tasha N. Blatt
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Satyawan Jadhav
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Usha N. Menon
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Paige N. Vinson
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Jerri M. Rook
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Shaun R. Stauffer
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Colleen M. Niswender
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Craig W. Lindsley
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C. David Weaver
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P. Jeffrey Conn
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Abstract

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants 1F32-NS049865, R01-NS031373]; the National Institutes of Health National Institute of Mental Health [Grants R01-MH062646, R01-MH074953]; and the National Institutes of Health National Institute on Drug Abuse [Grant 1R01-DA023947-01]. Vanderbilt is a center in 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.110.067207.

  • ABBREVIATIONS:

    CNS
    central nervous system
    mGluR
    metabotropic glutamate receptor
    PAM
    positive allosteric modulator
    ESI
    electrospray ionization
    NAM
    negative allosteric modulator
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    MPEP
    2-methyl-6-(phenylethynyl)pyridine hydrochloride
    NMDA
    N-methyl-d-aspartate
    DHPG
    dihydroxyphenylglycine
    SAR
    structure-activity relationship
    methoxyPEPy
    3-methoxy-5-(pyridin-2-ylethynyl)pyridine
    CDPPB
    3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
    HRMS
    high-resolution mass spectrometry
    CPPHA
    N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide
    5MPEP
    5-methyl-6-(phenylethynyl)pyridine
    HPLC
    high-performance liquid chromatography
    HEK
    human embryonic kidney
    DMEM
    Dulbecco's modified Eagle's medium
    PK
    pharmacokinetic
    PCP
    phencyclidine
    DMSO
    dimethyl sulfoxide
    FDSS
    functional drug screening system
    M1
    muscarinic receptor subtype 1
    Veh
    vehicle
    VI
    variable interval
    FBS
    fetal bovine serum
    CRC
    concentration-response curve
    MTEP
    3-((2-methyl-4-thiazolyl)ethynyl)pyridine
    HTS
    high-throughput screening
    BCD
    β-cyclodextrin
    ADX-47273
    S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone
    VU0366025
    (3-hydroxyazetidin-1-yl)(4-phenylehtynyl)phenyl)methanone
    VU0366028
    (4-((3,4-difluorophenyl)ethynyl)phenyl) (morpholino)methanone
    VU0366029
    (3-hydroxyazetidin-1-yl)(4-(3-fluorophenyl)ethynyl)phenyl)methanone
    VU0366024
    (4-methanolpiperidin-1-yl)(4-phenylethynyl)phenyl)methanone
    VU0366027
    (4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxymethyl)piperidin-1-yl)methanone
    VU0366030
    (4-((3-fluorophenyl)ethynyl)phenyl)(4-hydroxy-4-methylpiperidin-1-yl)methanone
    VU0040228
    5-(3,5-dimethoxyphenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole
    VU0285683
    3-fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile
    VU0255037
    5-(3-bromophenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole
    VU0067144
    5-(3-chlorophenyl)-3-(pyridine-2-yl)-1,2,4-oxadiazole
    VU0255038
    3-(pyridine-2-yl)-5-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole
    VU0092273
    (4-hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone
    VU0240381
    (4-morphonyl)(4-phenylethynyl)phenyl) methanone
    VU0366026
    (4-hydroxypiperidin-1-yl)(4-(3-fluorophenyl)ethynyl)phenyl)methanone
    VU0366031
    (4-morphonyl)(4-(3-fluorophenyl) ethynyl)phenyl)methanone
    VU0360175
    (6-((3-fluorophenyl)ethynyl)pyridin-3-yl)(morpholino)methanone
    VU0361747
    (6-((3-fluorophenyl)ethynyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone
    VU0360172
    N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide
    VU0029251
    2-(methylthio)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-amine
    VU0028316
    (E)-3-(3-(2-methyl-5-phenylfuran-3-carboxamido)phenyl)acrylic acid.

  • Received July 9, 2010.
  • Accepted October 4, 2010.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 78 (6)
Molecular Pharmacology
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1 Dec 2010
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Research ArticleArticle

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Alice L. Rodriguez, Mark D. Grier, Carrie K. Jones, Elizabeth J. Herman, Alexander S. Kane, Randy L. Smith, Richard Williams, Ya Zhou, Joy E. Marlo, Emily L. Days, Tasha N. Blatt, Satyawan Jadhav, Usha N. Menon, Paige N. Vinson, Jerri M. Rook, Shaun R. Stauffer, Colleen M. Niswender, Craig W. Lindsley, C. David Weaver and P. Jeffrey Conn
Molecular Pharmacology December 1, 2010, 78 (6) 1105-1123; DOI: https://doi.org/10.1124/mol.110.067207

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Research ArticleArticle

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Alice L. Rodriguez, Mark D. Grier, Carrie K. Jones, Elizabeth J. Herman, Alexander S. Kane, Randy L. Smith, Richard Williams, Ya Zhou, Joy E. Marlo, Emily L. Days, Tasha N. Blatt, Satyawan Jadhav, Usha N. Menon, Paige N. Vinson, Jerri M. Rook, Shaun R. Stauffer, Colleen M. Niswender, Craig W. Lindsley, C. David Weaver and P. Jeffrey Conn
Molecular Pharmacology December 1, 2010, 78 (6) 1105-1123; DOI: https://doi.org/10.1124/mol.110.067207
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