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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Els S,Schild E,Petersen PS,Kilian TM,Mokrosinski J,Frimurer TM,Chollet C,Schwartz TW,Holst B,Beck-Sickinger AG

doi

10.1021/jm300414b

subject

Has Abstract

pub_date

2012-09-13 00:00:00

pages

7437-49

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

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