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Research ArticleArticle

Allosteric Ligands of the Glucagon-Like Peptide 1 Receptor (GLP-1R) Differentially Modulate Endogenous and Exogenous Peptide Responses in a Pathway-Selective Manner: Implications for Drug Screening

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Rohan Sridhar, Owen L. Woodman, Laurence J. Miller, Roger J. Summers, Arthur Christopoulos and Patrick M. Sexton
Molecular Pharmacology September 2010, 78 (3) 456-465; DOI: https://doi.org/10.1124/mol.110.065664
Cassandra Koole
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Denise Wootten
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John Simms
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Celine Valant
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Rohan Sridhar
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Owen L. Woodman
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Laurence J. Miller
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Roger J. Summers
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Arthur Christopoulos
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Patrick M. Sexton
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Abstract

The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1–37) and truncated (7–37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca2+ mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.

Footnotes

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

  • This work was funded in part by the National Health and Medical Research Council (NHMRC) of Australia [Program Grant 519461]; and by an NHMRC of Australia Principal Research Fellowship (to P.M.S.) and a Senior Research Fellowship (to A.C.).

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

    doi:10.1124/mol.110.065664.

  • ABBREVIATIONS:

    DM
    diabetes mellitus
    GLP-1R
    glucagon-like peptide 1 receptor
    GPCR
    G protein-coupled receptor
    DPPIV
    dipeptidyl peptidase IV
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    ERK1/2
    extracellular signal-regulated kinases 1 and 2
    BCA
    bicinchoninic acid
    CHO
    Chinese hamster ovary
    BSA
    bovine serum albumin
    LY2033298
    3-amino-5-chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamide
    compound 2
    (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline
    GLP-1
    glucagon-like peptide 1.

  • Received April 16, 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

Allosteric Ligands of the Glucagon-Like Peptide 1 Receptor (GLP-1R) Differentially Modulate Endogenous and Exogenous Peptide Responses in a Pathway-Selective Manner: Implications for Drug Screening

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Rohan Sridhar, Owen L. Woodman, Laurence J. Miller, Roger J. Summers, Arthur Christopoulos and Patrick M. Sexton
Molecular Pharmacology September 1, 2010, 78 (3) 456-465; DOI: https://doi.org/10.1124/mol.110.065664

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Research ArticleArticle

Allosteric Ligands of the Glucagon-Like Peptide 1 Receptor (GLP-1R) Differentially Modulate Endogenous and Exogenous Peptide Responses in a Pathway-Selective Manner: Implications for Drug Screening

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Rohan Sridhar, Owen L. Woodman, Laurence J. Miller, Roger J. Summers, Arthur Christopoulos and Patrick M. Sexton
Molecular Pharmacology September 1, 2010, 78 (3) 456-465; DOI: https://doi.org/10.1124/mol.110.065664
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