title: An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor.
abstract: The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse agonism to agonism, indicating the importance of this sequence. Introduction of β-(3-benzothienyl)-d-alanine (d-Bth), 3,3-diphenyl-d-alanine (d-Dip) and 1-naphthyl-d-alanine (d-1-Nal) at position 2 resulted in highly potent and efficient inverse agonists, whereas the substitution of d-tryptophane at position 4 with 1-naphthyl-d-alanine (d-1-Nal) and 2-naphthyl-d-alanine (d-2-Nal) induces agonism in functional assays. Competitive binding studies showed a high affinity of the inverse agonist K-(d-1-Nal)-FwLL-NH(2) at the ghrelin receptor. Moreover, mutagenesis studies of the receptor revealed key positions for the switch between inverse agonist and agonist response. Hence, only minor changes in the peptide sequence can decide between agonism and inverse agonism and have a major impact on the biological activity.
authors.affiliation: Institute of Biochemistry, Universität Leipzig, Brüderstraße 34, 04103 Leipzig, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Els
authors.forename: Enrico
authors.initials: E
authors.lastname: Schild
authors.forename: Pia Steen
authors.initials: PS
authors.lastname: Petersen
authors.forename: Tom-Marten
authors.initials: TM
authors.lastname: Kilian
authors.forename: Jacek
authors.initials: J
authors.lastname: Mokrosinski
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Constance
authors.initials: C
authors.lastname: Chollet
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D009842:Oligopeptides; D054440:Receptors, Ghrelin