Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold

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

Standard

Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold. / Johansson, Henrik; Boesgaard, Michael Worch; Nørskov-Lauritsen, Lenea; Larsen, Inna; Kuhne, Sebastiaan; Gloriam, David E; Bräuner-Osborne, Hans; Sejer Pedersen, Daniel.

In: Journal of Medicinal Chemistry, Vol. 58, No. 22, 25.11.2015, p. 8938-51.

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

Harvard

Johansson, H, Boesgaard, MW, Nørskov-Lauritsen, L, Larsen, I, Kuhne, S, Gloriam, DE, Bräuner-Osborne, H & Sejer Pedersen, D 2015, 'Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold', Journal of Medicinal Chemistry, vol. 58, no. 22, pp. 8938-51. https://doi.org/10.1021/acs.jmedchem.5b01254

APA

Johansson, H., Boesgaard, M. W., Nørskov-Lauritsen, L., Larsen, I., Kuhne, S., Gloriam, D. E., Bräuner-Osborne, H., & Sejer Pedersen, D. (2015). Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold. Journal of Medicinal Chemistry, 58(22), 8938-51. https://doi.org/10.1021/acs.jmedchem.5b01254

Vancouver

Johansson H, Boesgaard MW, Nørskov-Lauritsen L, Larsen I, Kuhne S, Gloriam DE et al. Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold. Journal of Medicinal Chemistry. 2015 Nov 25;58(22):8938-51. https://doi.org/10.1021/acs.jmedchem.5b01254

Author

Johansson, Henrik ; Boesgaard, Michael Worch ; Nørskov-Lauritsen, Lenea ; Larsen, Inna ; Kuhne, Sebastiaan ; Gloriam, David E ; Bräuner-Osborne, Hans ; Sejer Pedersen, Daniel. / Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 22. pp. 8938-51.

Bibtex

@article{ef12bbcc8de742fcbd3192cb54ceaa16,
title = "Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold",
abstract = "G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.",
author = "Henrik Johansson and Boesgaard, {Michael Worch} and Lenea N{\o}rskov-Lauritsen and Inna Larsen and Sebastiaan Kuhne and Gloriam, {David E} and Hans Br{\"a}uner-Osborne and {Sejer Pedersen}, Daniel",
year = "2015",
month = nov,
day = "25",
doi = "10.1021/acs.jmedchem.5b01254",
language = "English",
volume = "58",
pages = "8938--51",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

RIS

TY - JOUR

T1 - Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold

AU - Johansson, Henrik

AU - Boesgaard, Michael Worch

AU - Nørskov-Lauritsen, Lenea

AU - Larsen, Inna

AU - Kuhne, Sebastiaan

AU - Gloriam, David E

AU - Bräuner-Osborne, Hans

AU - Sejer Pedersen, Daniel

PY - 2015/11/25

Y1 - 2015/11/25

N2 - G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.

AB - G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e, and 34b as antagonists at the GPRC6A receptor in the low micromolar range and show that 7 and 34b display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making 7 and 34b the most potent and selective antagonists for the GPRC6A receptor reported to date.

U2 - 10.1021/acs.jmedchem.5b01254

DO - 10.1021/acs.jmedchem.5b01254

M3 - Journal article

C2 - 26516782

VL - 58

SP - 8938

EP - 8951

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -

ID: 150328186