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Research ArticleDrug Discovery and Translational Medicine

The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease

Carrie K. Jones, Michael Bubser, Analisa D. Thompson, Jonathan W. Dickerson, Nathalie Turle-Lorenzo, Marianne Amalric, Anna L. Blobaum, Thomas M. Bridges, Ryan D. Morrison, Satyawan Jadhav, Darren W. Engers, Kimberly Italiano, Jacob Bode, J. Scott Daniels, Craig W. Lindsley, Corey R. Hopkins, P. Jeffrey Conn and Colleen M. Niswender
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 404-421; DOI: https://doi.org/10.1124/jpet.111.187443
Carrie K. Jones
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Michael Bubser
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Analisa D. Thompson
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Jonathan W. Dickerson
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Nathalie Turle-Lorenzo
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Marianne Amalric
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Anna L. Blobaum
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Thomas M. Bridges
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Ryan D. Morrison
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Satyawan Jadhav
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Darren W. Engers
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Kimberly Italiano
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Jacob Bode
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J. Scott Daniels
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Craig W. Lindsley
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Corey R. Hopkins
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P. Jeffrey Conn
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Colleen M. Niswender
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Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS048334, NS31373]; the National Institutes of Health National Institute of Mental Health [Grant MH084659]; the Michael J. Fox Foundation; and Era-Net NEURON [Grant ANR-08-NEUR-006-01]. Vanderbilt is a Specialized Chemistry Center within the Molecular Libraries Probe Centers Networks.

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

    http://dx.doi.org/10.1124/jpet.111.187443.

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

  • ABBREVIATIONS:

    PD
    Parkinson's disease
    A2A
    adenosine 2A
    BG
    basal ganglia
    FLA
    forelimb asymmetry
    mGlu
    metabotropic glutamate receptor
    PAM
    positive allosteric modulator
    SNc
    substantia nigra pars compacta
    SNr
    substantia nigra pars reticulata
    GPi
    internal globus pallidus
    GPe
    external globus pallidus
    STN
    subthalamic nucleus
    VU0155041
    (±)-cis-2-(3,5-dicholorphenylcarbamoyl)cyclohexanecarboxylic
    VU0364770
    N-(3-chlorophenyl)picolinamide
    VU0364772
    N-(6-(trifluoromethyl)pyridin-2-yl)picolinamide
    GPCR
    G protein-coupled receptor
    GIRK
    G protein-regulated inwardly rectifying K (potassium) channel
    HEK
    human embryonic kidney
    DMSO
    dimethyl sulfoxide
    6-OHDA
    6-hydroxydopamine
    HBSS
    Hanks' balanced salt solution
    DMEM
    Dulbecco's modified Eagle's medium
    DOPAC
    3,4-dihydroxyphenylacetic acid
    HVA
    homovanillic acid
    ANOVA
    analysis of variance
    MAO
    monoamine oxidase
    FBS
    fetal bovine serum
    LC
    liquid chromatography
    MS
    mass spectrometry
    CL
    clearance
    HPLC
    high-performance liquid chromatography
    AP
    anteroposterior
    TH
    tyrosine hydroxylase
    TBS
    Tris-buffered saline
    RT
    reaction time
    DA
    dopamine
    ESI
    electrospray ionization
    CRC
    concentration-response curve.

  • Received August 29, 2011.
  • Accepted November 15, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Research ArticleDrug Discovery and Translational Medicine

mGlu4 PAM in Preclinical Models of Parkinson's Disease

Carrie K. Jones, Michael Bubser, Analisa D. Thompson, Jonathan W. Dickerson, Nathalie Turle-Lorenzo, Marianne Amalric, Anna L. Blobaum, Thomas M. Bridges, Ryan D. Morrison, Satyawan Jadhav, Darren W. Engers, Kimberly Italiano, Jacob Bode, J. Scott Daniels, Craig W. Lindsley, Corey R. Hopkins, P. Jeffrey Conn and Colleen M. Niswender
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 404-421; DOI: https://doi.org/10.1124/jpet.111.187443

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Research ArticleDrug Discovery and Translational Medicine

mGlu4 PAM in Preclinical Models of Parkinson's Disease

Carrie K. Jones, Michael Bubser, Analisa D. Thompson, Jonathan W. Dickerson, Nathalie Turle-Lorenzo, Marianne Amalric, Anna L. Blobaum, Thomas M. Bridges, Ryan D. Morrison, Satyawan Jadhav, Darren W. Engers, Kimberly Italiano, Jacob Bode, J. Scott Daniels, Craig W. Lindsley, Corey R. Hopkins, P. Jeffrey Conn and Colleen M. Niswender
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 404-421; DOI: https://doi.org/10.1124/jpet.111.187443
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