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

Henrik Johansson; Michael Worch Boesgaard; Lenea Nørskov-Lauritsen; Inna Larsen; Sebastiaan Kuhne; David E Gloriam; Hans Bräuner-Osborne; Daniel Sejer Pedersen

doi:10.1021/acs.jmedchem.5b01254

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

Henrik Johansson, Michael Worch Boesgaard, Lenea Nørskov-Lauritsen, Inna Larsen, Sebastiaan Kuhne, David E Gloriam, Hans Bräuner-Osborne, Daniel Sejer Pedersen

Department of Drug Design and Pharmacology

16 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	22
Pages (from-to)	8938-51
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01254
Publication status	Published - 25 Nov 2015

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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

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 et al.
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

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

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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.",

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AU - Johansson, Henrik

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AU - Nørskov-Lauritsen, Lenea

AU - Larsen, Inna

AU - Kuhne, Sebastiaan

AU - Gloriam, David E

AU - Bräuner-Osborne, Hans

AU - Sejer Pedersen, Daniel

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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.

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ER -

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

Abstract

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