Species-specific differences in agonistic activity of ago-allosteric modulators toward glucagon-like peptide 2 receptor.

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 (GPCR) coupled with Gα(s). Few small-molecule agonists had been reported for class-B GPCRs, but we recently reported the first scaffold compounds of ago-allosteric modulators for human GLP-2R. Methyl 2-{[(2Z)-2-(2,5-dichlorothiophen- 3-yl)-2-(hydroxyimino)ethyl]sulfanyl}benzoate (compound 1) and its de-esterified derivative (compound 2) induced placental alkaline phosphatase (PLAP) activity in HEK293 cells overexpressing human GLP-2R and PLAP driven by cAMP response element. In this study, we observed that rat, Syrian hamster, and dog GLP-2Rs also responded to compounds 1 and 2 in the same reporter system. However, no agonistic activity of the compounds toward mouse GLP-2R was detected. Mutagenesis studies showed that mutant human GLP-2Rs with Pro392Leu substitution of mouse GLP-2R for human GLP-2R amino acid residues nullified the PLAP activity of compound 2, although these mutant receptors responded to GLP-2. This finding suggests that the Pro392 residue of human GLP-2R is essential for the agonistic activity of compound 2.

Cite this paper

@article{Yamazaki2012SpeciesspecificDI, title={Species-specific differences in agonistic activity of ago-allosteric modulators toward glucagon-like peptide 2 receptor.}, author={Kazuto Yamazaki and Kazuma Takase and Misako Watanabe and Takaki Kagaya and Hiroki Terauchi and Daisuke Iida and Hironori Fukumoto and Shuichi Suzuki and Tohru Arai and Mika Aoki and Takashi Seiki and Kappei Tsukahara and Junichi Nagakawa}, journal={Biomedical research}, year={2012}, volume={33 6}, pages={337-44} }