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Research ArticleArticle

Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators

Celine Valant, Luigi Aurelio, Vijay B. Urmaliya, Paul White, Peter J. Scammells, Patrick M. Sexton and Arthur Christopoulos
Molecular Pharmacology September 2010, 78 (3) 444-455; DOI: https://doi.org/10.1124/mol.110.064568
Celine Valant
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Luigi Aurelio
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Vijay B. Urmaliya
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Paul White
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Peter J. Scammells
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Patrick M. Sexton
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Arthur Christopoulos
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Abstract

Despite the identification of 2-amino-3-benzoylthiophenes (2A3BTs) as the first example of small-molecule allosteric potentiators of agonist function at a G protein-coupled receptor (GPCR)—the adenosine A1 receptor—their mechanism of action is still not fully understood. We now report the mechanistic basis for the complex behaviors noted for 2A3BTs at A1 receptors. Using a combination of membrane-based and intact-cell radioligand binding, multiple signaling assays, and a native tissue bioassay, we found that the allosteric interaction between 2A3BTs and the agonists 2-chloro-N6-[3H]cyclopentyladenosine or (−)-N6-(2-phenylisopropyl)adenosine (R-PIA) or the antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine is consistent with a ternary complex model involving recognition of a single extracellular allosteric site. However, when allowed access to the intracellular milieu, 2A3BTs have a secondary action as direct G protein inhibitors; this latter property is receptor-independent as it is observed in nontransfected cells and also after stimulation of another GPCR. In addition, we found that 2A3BTs can signal as allosteric agonists in their own right but show bias toward certain pathways relative to the orthosteric agonist, R-PIA. These results indicate that 2A3BTs have a dual mode of action when interacting with the A1 receptor and that they can engender novel functional selectivity in A1 signaling. These mechanisms need to be factored into allosteric ligand structure-activity studies.

Footnotes

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

  • This work was funded by the National Health and Medical Research Council (NHMRC) of Australia [Program Grant 519461]; the Australian Research Council [Discovery Grant DP0877497]; and by NHMRC Senior (to A.C.) and Principal (to P.M.S.) Research Fellowships.

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

    doi:10.1124/mol.110.064568.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    2A3BT
    2-amino-3-benzoylthiophene
    T62
    2-amino-4,5-dimethyl-3-thienyl-[3-(trifluoromethyl)phenyl]methanone
    PD81,723
    2-amino-4,5-dimethyl-3-thienyl-[3-(trifluoromethyl)phenyl]methanone
    LUF5484
    2-amino-(4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone
    VCP520
    2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanon
    VCP333
    tert-butyl 2-amino-3-(4-chlorobenzoyl)-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate
    FBS
    fetal bovine serum
    CCPA
    2-chloro-N6-cyclopentyladenosine
    DPCPX
    8-cyclopentyl-1,3-dipropylxanthine
    [35S]GTPγS
    guanosine 5′-O-[γ-[35S]thio]triphosphate
    ERK
    extracellular signal-regulated kinase
    CHO
    Chinese hamster ovary
    FBS
    fetal bovine serum
    Gpp(NH)p
    guanosine 5′-(β,γ-imido)triphosphate
    ATCM
    allosteric ternary complex mode
    R-PIA
    (−)-N6-(2-phenylisopropyl)adenosine.

  • Received March 8, 2010.
  • Accepted June 14, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (3)
Molecular Pharmacology
Vol. 78, Issue 3
1 Sep 2010
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Research ArticleArticle

Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators

Celine Valant, Luigi Aurelio, Vijay B. Urmaliya, Paul White, Peter J. Scammells, Patrick M. Sexton and Arthur Christopoulos
Molecular Pharmacology September 1, 2010, 78 (3) 444-455; DOI: https://doi.org/10.1124/mol.110.064568

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Research ArticleArticle

Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators

Celine Valant, Luigi Aurelio, Vijay B. Urmaliya, Paul White, Peter J. Scammells, Patrick M. Sexton and Arthur Christopoulos
Molecular Pharmacology September 1, 2010, 78 (3) 444-455; DOI: https://doi.org/10.1124/mol.110.064568
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