title: The role of C-terminal part of ghrelin in pharmacokinetic profile and biological activity in rats.
abstract: Ghrelin is an endogenous ligand for growth hormone secretagogue receptor 1a (GHS-R1a), and consists of 28 amino acid residues with octanoyl modification at Ser(3). The previous studies have revealed that N-terminal part of ghrelin including modified Ser(3) is the active core for the activation of GHS-R1a. On the other hand, the role of C-terminal (8-28) region in ghrelin has not been clarified yet. In the present study, we prepared human ghrelin, C-terminal truncated ghrelin derivatives and anamorelin, a small molecular GHS compound which supposedly mimics the N-terminal active core, and examined GHS-R1a agonist activity in vitro, pharmacokinetic (PK) profile and growth hormone (GH) releasing activity in rats. All compounds demonstrated potent GHS-R1a agonist activities in vitro. Although the lack of C-terminal two amino acids did not modify PK profile and GH releasing activity, the deletion of C-terminal 8 and 20 amino acids affected them, and ghrelin(1-7)-Lys-NH(2) exhibited very short plasma half-life and low GH releasing activity in vivo. In rat plasma, ghrelin(1-7)-Lys-NH(2) was degraded more rapidly than ghrelin, suggesting that C-terminal part of ghrelin protected octanoylation of Ser(3) from plasma esterases. Subdiaphragmatic vagotomy significantly attenuated GH response to ghrelin but not to anamorelin. These results suggest that the C-terminal part of ghrelin has an important role in the biological activity in vivo. We also found that ghrelin stimulated GH release mainly via a vagal nerve pathway but anamorelin augmented GH release possibly by directly acting on brain in rats.
authors.affiliation: Faculty of Pharmacology I, Asubio Pharma Co, Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Morozumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hanada
authors.forename: Hiromi
authors.initials: H
authors.lastname: Habara
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Furuya
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakatsuka
authors.forename: Norio
authors.initials: N
authors.lastname: Inomata
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Minamitake
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohsuye
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004355:Drug Stability; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D054439:Ghrelin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013006:Growth Hormone / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists / Q000378:metabolism; D014628:Vagotomy
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin; D013006:Growth Hormone; D002118:Calcium