Development and Characterization of Potent Succinate Receptor Fluorescent Tracers

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

Standard

Development and Characterization of Potent Succinate Receptor Fluorescent Tracers. / Ciba, Marija; Dibnah, Bethany; Hudson, Brian D.; Rexen Ulven, Elisabeth.

In: Journal of Medicinal Chemistry, Vol. 66, No. 13, 2023, p. 8951–8974.

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

Harvard

Ciba, M, Dibnah, B, Hudson, BD & Rexen Ulven, E 2023, 'Development and Characterization of Potent Succinate Receptor Fluorescent Tracers', Journal of Medicinal Chemistry, vol. 66, no. 13, pp. 8951–8974. https://doi.org/10.1021/acs.jmedchem.3c00552

APA

Ciba, M., Dibnah, B., Hudson, B. D., & Rexen Ulven, E. (2023). Development and Characterization of Potent Succinate Receptor Fluorescent Tracers. Journal of Medicinal Chemistry, 66(13), 8951–8974. https://doi.org/10.1021/acs.jmedchem.3c00552

Vancouver

Ciba M, Dibnah B, Hudson BD, Rexen Ulven E. Development and Characterization of Potent Succinate Receptor Fluorescent Tracers. Journal of Medicinal Chemistry. 2023;66(13):8951–8974. https://doi.org/10.1021/acs.jmedchem.3c00552

Author

Ciba, Marija ; Dibnah, Bethany ; Hudson, Brian D. ; Rexen Ulven, Elisabeth. / Development and Characterization of Potent Succinate Receptor Fluorescent Tracers. In: Journal of Medicinal Chemistry. 2023 ; Vol. 66, No. 13. pp. 8951–8974.

Bibtex

@article{2010837b8a9e4baab87f8971c02fd5bb,
title = "Development and Characterization of Potent Succinate Receptor Fluorescent Tracers",
abstract = "The succinate receptor (SUCNR1) has emerged as a potential target for the treatment of various metabolic and inflammatory diseases, including hypertension, inflammatory bowel disease, and rheumatoid arthritis. While several ligands for this receptor have been reported, species differences in pharmacology between human and rodent orthologs have limited the validation of SUCNR1's therapeutic potential. Here, we describe the development of the first potent fluorescent tool compounds for SUCNR1 and use these to define key differences in ligand binding to human and mouse SUCNR1. Starting from known agonist scaffolds, we developed a potent agonist tracer, TUG-2384 (22), with affinity for both human and mouse SUCNR1. In addition, we developed a novel antagonist tracer, TUG-2465 (46), which displayed high affinity for human SUCNR1. Using 46 we demonstrate that three humanizing mutations on mouse SUCNR1, N181.31E, K2697.32N, and G84EL1W, are sufficient to restore high-affinity binding of SUCNR1 antagonists to the mouse receptor ortholog. ",
author = "Marija Ciba and Bethany Dibnah and Hudson, {Brian D.} and {Rexen Ulven}, Elisabeth",
note = "Funding Information: This work was supported by the Lundbeck Foundation (ERU, grant no. R307-2018-2950) and by the Academy of Medical Sciences (BDH, grant no. SBF004\1033). ",
year = "2023",
doi = "10.1021/acs.jmedchem.3c00552",
language = "English",
volume = "66",
pages = "8951–8974",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "13",

}

RIS

TY - JOUR

T1 - Development and Characterization of Potent Succinate Receptor Fluorescent Tracers

AU - Ciba, Marija

AU - Dibnah, Bethany

AU - Hudson, Brian D.

AU - Rexen Ulven, Elisabeth

N1 - Funding Information: This work was supported by the Lundbeck Foundation (ERU, grant no. R307-2018-2950) and by the Academy of Medical Sciences (BDH, grant no. SBF004\1033).

PY - 2023

Y1 - 2023

N2 - The succinate receptor (SUCNR1) has emerged as a potential target for the treatment of various metabolic and inflammatory diseases, including hypertension, inflammatory bowel disease, and rheumatoid arthritis. While several ligands for this receptor have been reported, species differences in pharmacology between human and rodent orthologs have limited the validation of SUCNR1's therapeutic potential. Here, we describe the development of the first potent fluorescent tool compounds for SUCNR1 and use these to define key differences in ligand binding to human and mouse SUCNR1. Starting from known agonist scaffolds, we developed a potent agonist tracer, TUG-2384 (22), with affinity for both human and mouse SUCNR1. In addition, we developed a novel antagonist tracer, TUG-2465 (46), which displayed high affinity for human SUCNR1. Using 46 we demonstrate that three humanizing mutations on mouse SUCNR1, N181.31E, K2697.32N, and G84EL1W, are sufficient to restore high-affinity binding of SUCNR1 antagonists to the mouse receptor ortholog.

AB - The succinate receptor (SUCNR1) has emerged as a potential target for the treatment of various metabolic and inflammatory diseases, including hypertension, inflammatory bowel disease, and rheumatoid arthritis. While several ligands for this receptor have been reported, species differences in pharmacology between human and rodent orthologs have limited the validation of SUCNR1's therapeutic potential. Here, we describe the development of the first potent fluorescent tool compounds for SUCNR1 and use these to define key differences in ligand binding to human and mouse SUCNR1. Starting from known agonist scaffolds, we developed a potent agonist tracer, TUG-2384 (22), with affinity for both human and mouse SUCNR1. In addition, we developed a novel antagonist tracer, TUG-2465 (46), which displayed high affinity for human SUCNR1. Using 46 we demonstrate that three humanizing mutations on mouse SUCNR1, N181.31E, K2697.32N, and G84EL1W, are sufficient to restore high-affinity binding of SUCNR1 antagonists to the mouse receptor ortholog.

U2 - 10.1021/acs.jmedchem.3c00552

DO - 10.1021/acs.jmedchem.3c00552

M3 - Journal article

C2 - 37318348

AN - SCOPUS:85163613005

VL - 66

SP - 8951

EP - 8974

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 13

ER -

ID: 360026803