title: 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.
authors.affiliation: Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai, Tsukuba, Ibaraki, Japan. k5-yamazaki@hhc.eisai.co.jp
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Kazuma
authors.initials: K
authors.lastname: Takase
authors.forename: Misako
authors.initials: M
authors.lastname: Watanabe
authors.forename: Takaki
authors.initials: T
authors.lastname: Kagaya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Terauchi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iida
authors.forename: Hironori
authors.initials: H
authors.lastname: Fukumoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Tohru
authors.initials: T
authors.lastname: Arai
authors.forename: Mika
authors.initials: M
authors.lastname: Aoki
authors.forename: Takashi
authors.initials: T
authors.lastname: Seiki
authors.forename: Kappei
authors.initials: K
authors.lastname: Tsukahara
authors.forename: Junichi
authors.initials: J
authors.lastname: Nagakawa
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004285:Dogs; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D000067758:Glucagon-Like Peptide-2 Receptor; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D013045:Species Specificity
chemical_list: D058851:GPI-Linked Proteins; D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D007527:Isoenzymes; D018027:Receptors, Glucagon; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental