An Aromatic Region To Induce a Switch between Agonism and Inverse Agonism at the Ghrelin Receptor

详细信息    查看全文

• 作者：Sylvia Els ; Enrico Schild ; Pia Steen Petersen ; Tom-Marten Kilian ; Jacek Mokrosinski ; Thomas M. Frimurer ; Constance Chollet ; Thue W. Schwartz ; Birgitte Holst ; Annette G. Beck-Sickinger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7437-7449
• 全文大小：579K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

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-NH₂ that can swap the peptide behavior from inverse agonism to agonism, indicating the importance of this sequence. Introduction of 尾-(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-NH₂ 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.