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Research ArticleDrug Discovery and Translational Medicine

The Metabotropic Glutamate Receptor 7 Allosteric Modulator AMN082: A Monoaminergic Agent in Disguise?

Stacey J. Sukoff Rizzo, Sarah K. Leonard, Adam Gilbert, Paul Dollings, Deborah L. Smith, Mei-Yi Zhang, Li Di, Brian J. Platt, Sarah Neal, Jason M. Dwyer, Corey N. Bender, Jean Zhang, Tim Lock, Dianne Kowal, Angela Kramer, Andrew Randall, Christine Huselton, Karthick Vishwanathan, Susanna Y. Tse, John Butera, Robert H. Ring, Sharon Rosenzweig-Lipson, Zoë A. Hughes and John Dunlop
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 345-352; DOI: https://doi.org/10.1124/jpet.110.177378
Stacey J. Sukoff Rizzo
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Sarah K. Leonard
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Adam Gilbert
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Paul Dollings
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Deborah L. Smith
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Mei-Yi Zhang
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Li Di
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Brian J. Platt
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Sarah Neal
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Jason M. Dwyer
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Corey N. Bender
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Jean Zhang
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Tim Lock
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Dianne Kowal
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Angela Kramer
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Andrew Randall
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Christine Huselton
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Karthick Vishwanathan
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Susanna Y. Tse
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John Butera
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Robert H. Ring
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Sharon Rosenzweig-Lipson
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Zoë A. Hughes
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Abstract

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712–18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t1/2 < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.

Footnotes

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

    doi:10.1124/jpet.110.177378.

  • ABBREVIATIONS:

    mGlu
    metabotropic glutamate
    mGluR
    mGlu receptor
    CNS
    central nervous system
    AMN082
    N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride
    Met-1
    metabolite 1 (N-benzhydrylethane-1,2-diamine)
    AUC0-t
    area under the curve at last observed time point
    tmax
    time at maximum concentration
    Cmax
    maximum concentration
    LC
    liquid chromatography
    HPLC
    high-performance LC
    MS
    mass spectrometry
    SERT
    serotonin transporter
    NET
    norepinephrine transporter
    DAT
    dopamine transporter
    DASB
    N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine
    SSRI
    selective serotonin reuptake inhibitor
    ANOVA
    analysis of variance
    KO
    knockout
    ACN
    acetonitrile
    RLM
    rat liver microsomes
    CHO
    Chinese hamster ovary
    WIN 35428
    2β-carbomethoxy-3β-(4-fluorophenyl)tropane
    L-AP4
    (2S)-2-amino-4-phosphonobutanoic acid
    ESI
    electrospray ionization
    i.p.
    intraperitoneally
    5-HT
    5-hydroxytryptamine.

  • Received November 21, 2010.
  • Accepted April 12, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleDrug Discovery and Translational Medicine

The Metabotropic Glutamate Receptor 7 Allosteric Modulator AMN082: A Monoaminergic Agent in Disguise?

Stacey J. Sukoff Rizzo, Sarah K. Leonard, Adam Gilbert, Paul Dollings, Deborah L. Smith, Mei-Yi Zhang, Li Di, Brian J. Platt, Sarah Neal, Jason M. Dwyer, Corey N. Bender, Jean Zhang, Tim Lock, Dianne Kowal, Angela Kramer, Andrew Randall, Christine Huselton, Karthick Vishwanathan, Susanna Y. Tse, John Butera, Robert H. Ring, Sharon Rosenzweig-Lipson, Zoë A. Hughes and John Dunlop
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 345-352; DOI: https://doi.org/10.1124/jpet.110.177378

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Research ArticleDrug Discovery and Translational Medicine

The Metabotropic Glutamate Receptor 7 Allosteric Modulator AMN082: A Monoaminergic Agent in Disguise?

Stacey J. Sukoff Rizzo, Sarah K. Leonard, Adam Gilbert, Paul Dollings, Deborah L. Smith, Mei-Yi Zhang, Li Di, Brian J. Platt, Sarah Neal, Jason M. Dwyer, Corey N. Bender, Jean Zhang, Tim Lock, Dianne Kowal, Angela Kramer, Andrew Randall, Christine Huselton, Karthick Vishwanathan, Susanna Y. Tse, John Butera, Robert H. Ring, Sharon Rosenzweig-Lipson, Zoë A. Hughes and John Dunlop
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 345-352; DOI: https://doi.org/10.1124/jpet.110.177378
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