title: A novel truncated glucagon-like peptide 2 (GLP-2) as a tool for analyzing GLP-2 receptor agonists.
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.
authors.affiliation: Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan. k5-yamazaki@hhc.eisai.co.jp
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Takaki
authors.initials: T
authors.lastname: Kagaya
authors.forename: Misako
authors.initials: M
authors.lastname: Watanabe
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: Kazuma
authors.initials: K
authors.lastname: Takase
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 / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D053767:Glucagon-Like Peptide 2 / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D000067758:Glucagon-Like Peptide-2 Receptor; D057809:HEK293 Cells; D006801:Humans; D019811:Hydroxylamine / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008252:Macaca fascicularis; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013045:Species Specificity; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; C585767:N-(1-(2,5-dichlorothiophen-3-yl)-2-(phenylsulfanyl)ethylidene)hydroxylamine; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D013876:Thiophenes; D019811:Hydroxylamine; D000242:Cyclic AMP; D000469:Alkaline Phosphatase