title: Small molecule allosteric modulation of the glucagon-like Peptide-1 receptor enhances the insulinotropic effect of oxyntomodulin.
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.
authors.affiliation: Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Willard
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Showalter
authors.forename: Emilia E
authors.initials: EE
authors.lastname: Savage
authors.forename: James
authors.initials: J
authors.lastname: Ficorilli
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Farb
authors.forename: Krister
authors.initials: K
authors.lastname: Bokvist
authors.forename: Jorge
authors.initials: J
authors.lastname: Alsina-Fernandez
authors.forename: Sebastian G B
authors.initials: SG
authors.lastname: Furness
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Sloop
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D053772:Oxyntomodulin / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D019204:GTP-Binding Proteins