An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. / Els, Sylvia; Schild, Enrico; Petersen, Pia Steen; Kilian, Tom-Marten; Mokrosinski, Jacek; Frimurer, Thomas M; Chollet, Constance; Schwartz, Thue W; Holst, Birgitte; Beck-Sickinger, Annette G.

In: Journal of Medicinal Chemistry, Vol. 55, No. 17, 13.09.2012, p. 7437-49.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Els, S, Schild, E, Petersen, PS, Kilian, T-M, Mokrosinski, J, Frimurer, TM, Chollet, C, Schwartz, TW, Holst, B & Beck-Sickinger, AG 2012, 'An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor', Journal of Medicinal Chemistry, vol. 55, no. 17, pp. 7437-49. https://doi.org/10.1021/jm300414b

APA

Els, S., Schild, E., Petersen, P. S., Kilian, T-M., Mokrosinski, J., Frimurer, T. M., Chollet, C., Schwartz, T. W., Holst, B., & Beck-Sickinger, A. G. (2012). An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. Journal of Medicinal Chemistry, 55(17), 7437-49. https://doi.org/10.1021/jm300414b

Vancouver

Els S, Schild E, Petersen PS, Kilian T-M, Mokrosinski J, Frimurer TM et al. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. Journal of Medicinal Chemistry. 2012 Sep 13;55(17):7437-49. https://doi.org/10.1021/jm300414b

Author

Els, Sylvia ; Schild, Enrico ; Petersen, Pia Steen ; Kilian, Tom-Marten ; Mokrosinski, Jacek ; Frimurer, Thomas M ; Chollet, Constance ; Schwartz, Thue W ; Holst, Birgitte ; Beck-Sickinger, Annette G. / An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 17. pp. 7437-49.

Bibtex

@article{fdd83fefed5b4d12a3c970d48af6e597,
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.",
keywords = "Animals, COS Cells, Cercopithecus aethiops, Feeding Behavior, Humans, Models, Molecular, Mutagenesis, Oligopeptides, Rats, Receptors, Ghrelin",
author = "Sylvia Els and Enrico Schild and Petersen, {Pia Steen} and Tom-Marten Kilian and Jacek Mokrosinski and Frimurer, {Thomas M} and Constance Chollet and Schwartz, {Thue W} and Birgitte Holst and Beck-Sickinger, {Annette G}",
year = "2012",
month = sep,
day = "13",
doi = "10.1021/jm300414b",
language = "English",
volume = "55",
pages = "7437--49",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

RIS

TY - JOUR

T1 - An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor

AU - Els, Sylvia

AU - Schild, Enrico

AU - Petersen, Pia Steen

AU - Kilian, Tom-Marten

AU - Mokrosinski, Jacek

AU - Frimurer, Thomas M

AU - Chollet, Constance

AU - Schwartz, Thue W

AU - Holst, Birgitte

AU - Beck-Sickinger, Annette G

PY - 2012/9/13

Y1 - 2012/9/13

N2 - 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.

AB - 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.

KW - Animals

KW - COS Cells

KW - Cercopithecus aethiops

KW - Feeding Behavior

KW - Humans

KW - Models, Molecular

KW - Mutagenesis

KW - Oligopeptides

KW - Rats

KW - Receptors, Ghrelin

U2 - 10.1021/jm300414b

DO - 10.1021/jm300414b

M3 - Journal article

C2 - 22920150

VL - 55

SP - 7437

EP - 7449

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -

ID: 47525561