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Molecular Pharmacology

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Research ArticleArticle

Small Molecule Allosteric Modulation of the Glucagon-Like Peptide-1 Receptor Enhances the Insulinotropic Effect of Oxyntomodulin

Francis S. Willard, Denise Wootten, Aaron D. Showalter, Emilia E. Savage, James Ficorilli, Thomas B. Farb, Krister Bokvist, Jorge Alsina-Fernandez, Sebastian G. B. Furness, Arthur Christopoulos, Patrick M. Sexton and Kyle W. Sloop
Molecular Pharmacology December 2012, 82 (6) 1066-1073; DOI: https://doi.org/10.1124/mol.112.080432
Francis S. Willard
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Denise Wootten
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Aaron D. Showalter
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Emilia E. Savage
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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James Ficorilli
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Thomas B. Farb
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Krister Bokvist
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Jorge Alsina-Fernandez
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Sebastian G. B. Furness
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Arthur Christopoulos
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Patrick M. Sexton
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Kyle W. Sloop
Translational Science and Technologies (F.S.W.), Endocrine Discovery (A.D.S., J.F., T.B.F., K.B., K.W.S.), and BioTechnology Discovery Research (J.A.-F.), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (D.W., E.E.S., S.G.B.F., A.C., P.M.S.)
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Abstract

Identifying novel mechanisms to enhance glucagon-like peptide-1 (GLP-1) receptor signaling may enable nascent medicinal chemistry strategies with the aim of developing new orally available therapeutic agents for the treatment of type 2 diabetes mellitus. Therefore, we tested the hypothesis that selectively modulating the low-affinity GLP-1 receptor agonist, oxyntomodulin, would improve the insulin secretory properties of this naturally occurring hormone to provide a rationale for pursuing an unexplored therapeutic approach. Signal transduction and competition binding studies were used to investigate oxyntomodulin activity on the GLP-1 receptor in the presence of the small molecule GLP-1 receptor modulator, 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP). In vivo, the intravenous glucose tolerance test characterized oxyntomodulin-induced insulin secretion in animals administered the small molecule. BETP increased oxyntomodulin binding affinity for the GLP-1 receptor and enhanced oxyntomodulin-mediated GLP-1 receptor signaling as measured by activation of the α subunit of heterotrimeric G protein and cAMP accumulation. In addition, oxyntomodulin-induced insulin secretion was enhanced in the presence of the compound. BETP was pharmacologically characterized to induce biased signaling by oxyntomodulin. These studies demonstrate that small molecules targeting the GLP-1 receptor can increase binding and receptor activation of the endogenous peptide oxyntomodulin. The biased signaling engendered by BETP suggests that GLP-1 receptor mobilization of cAMP is the critical insulinotropic signaling event. Because of the unique metabolic properties of oxyntomodulin, identifying molecules that enhance its activity should be pursued to assess the efficacy and safety of this novel mechanism.

Footnotes

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

  • This work was supported in part by the National Health and Medical Research Council of Australia [Project Grant 1002180, Program Grant 519461].

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

    http://dx.doi.org/10.1124/mol.112.080432.

  • ABBREVIATIONS:

    GLP-1
    glucagon-like peptide-1
    CNS
    central nervous system
    GPCR
    G protein-coupled receptor
    ERK1/2
    extracellular signal-regulated kinases 1 and 2
    DPP-4
    dipeptidyl peptidase-4
    BETP
    4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine
    HEK
    human embryonic kidney
    CHO
    Chinese hamster ovary
    Rluc
    Renilla luciferase
    BRET
    bioluminescence resonance energy transfer
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    IVGTT
    intravenous glucose tolerance test
    HHB
    hypotonic homogenization buffer.

  • Received June 8, 2012.
  • Accepted August 28, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Allosteric Modulation of Oxyntomodulin at the GLP-1 Receptor

Francis S. Willard, Denise Wootten, Aaron D. Showalter, Emilia E. Savage, James Ficorilli, Thomas B. Farb, Krister Bokvist, Jorge Alsina-Fernandez, Sebastian G. B. Furness, Arthur Christopoulos, Patrick M. Sexton and Kyle W. Sloop
Molecular Pharmacology December 1, 2012, 82 (6) 1066-1073; DOI: https://doi.org/10.1124/mol.112.080432

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Research ArticleArticle

Allosteric Modulation of Oxyntomodulin at the GLP-1 Receptor

Francis S. Willard, Denise Wootten, Aaron D. Showalter, Emilia E. Savage, James Ficorilli, Thomas B. Farb, Krister Bokvist, Jorge Alsina-Fernandez, Sebastian G. B. Furness, Arthur Christopoulos, Patrick M. Sexton and Kyle W. Sloop
Molecular Pharmacology December 1, 2012, 82 (6) 1066-1073; DOI: https://doi.org/10.1124/mol.112.080432
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