A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists

Biomed Res. 2013 Jun;34(3):129-36. doi: 10.2220/biomedres.34.129.

Abstract

Glucagon-like peptide 2 (GLP-2) is an intestinotropic peptide that binds to GLP-2 receptor (GLP-2R), a class-B G protein-coupled receptor. The GLP-2R antagonist GLP-2(3-33) has relatively high partial agonistic activity, and there are as yet no ideal known potent GLP-2R antagonists. We therefore prepared several truncated forms of human GLP-2 and characterized them by binding and reporter assays to find antagonists more potent than GLP-2(3-33). We found that GLP-2(11-33) was the most potent orthosteric GLP-2R antagonist, with binding activity almost equal to those of GLP-2 and GLP-2(3-33) and weaker intrinsic agonistic activity than GLP-2(3-33). GLP-2(11-33) retained weak agonistic activity toward human, cynomolgus monkey, dog, and Syrian hamster GLP-2Rs. However, it had no agonistic activity toward rat GLP-2R. GLP-2(11-33) potentiated the agonistic activity of an ago-allosteric modulator of GLP-2R, compound 1 (N-[1-(2,5-dichlorothiophen-3-yl)-2-(phenylsulfanyl)ethylidene]hydroxylamine), synergistically toward human GLP-2R. In the case of rat GLP-2R, GLP-2(11-33) decreased the agonistic activity of compound 1, although GLP-2 and GLP-2(3-33) increased this activity additively. These findings suggest that the binding sites of the ago-allosteric modulator and GLP-2 overlap, at least in rat GLP-2R. GLP-2(11-33) is a novel, useful tool for analyzing the mode of action of agonists and ago-allosteric modulators of GLP-2R.

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Allosteric Regulation
  • Animals
  • Cricetinae
  • Cyclic AMP / metabolism
  • Dogs
  • Glucagon-Like Peptide 2 / chemistry*
  • Glucagon-Like Peptide 2 / genetics
  • Glucagon-Like Peptide 2 / pharmacology
  • Glucagon-Like Peptide-2 Receptor
  • HEK293 Cells
  • Humans
  • Hydroxylamine / chemical synthesis
  • Hydroxylamine / pharmacology
  • Kinetics
  • Macaca fascicularis
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology
  • Protein Binding
  • Rats
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / antagonists & inhibitors*
  • Receptors, Glucagon / metabolism
  • Species Specificity
  • Thiophenes / chemical synthesis
  • Thiophenes / pharmacology

Substances

  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-2 Receptor
  • N-(1-(2,5-dichlorothiophen-3-yl)-2-(phenylsulfanyl)ethylidene)hydroxylamine
  • Peptide Fragments
  • Receptors, Glucagon
  • Thiophenes
  • Hydroxylamine
  • Cyclic AMP
  • Alkaline Phosphatase