Small molecule allosteric modulation of the glucagon-like Peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin

Francis S Willard, Denise L Wootten, Aaron D Showalter, Emilia Elizabeth Savage, James Ficorilli, Thomas B Farb, Krister Bokvist, Jorge Alsina-Fernandez, Sebastian GB Furness, Arthur Christopoulos, Patrick M Sexton, Kyle W Sloop

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Identifying novel mechanisms to enhance glucagon-like peptide-1 (GLP-1) receptor signaling may enable nascent medicinal chemistry strategies aimed at 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 alpha 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 GLP-1 receptor mobilization of cAMP is the critical insulinotropic signaling event. Due to unique metabolic properties of oxyntomodulin, identifying molecules that enhance its activity should be pursued in order to assess the efficacy and safety of this novel mechanism.
Original languageEnglish
Pages (from-to)1066 - 1073
Number of pages8
JournalMolecular Pharmacology
Issue number6
Publication statusPublished - 2012

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