Ciba, M., Dibnah, B., Hudson, B. D. and Ulven, E. R. (2023) Development and characterization of potent succinate receptor fluorescent tracers. Journal of Medicinal Chemistry, 66(13), pp. 8951-8974. (doi: 10.1021/acs.jmedchem.3c00552) (PMID:37318348)
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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.
| Item Type: | Articles |
|---|---|
| Additional 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). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Ciba, Marija and Hudson, Dr Brian and Dibnah, Miss Beth |
| Authors: | Ciba, M., Dibnah, B., Hudson, B. D., and Ulven, E. R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Journal of Medicinal Chemistry |
| Publisher: | American Chemical Society |
| ISSN: | 0022-2623 |
| ISSN (Online): | 1520-4804 |
| Published Online: | 15 June 2023 |
| Copyright Holders: | Copyright © 2023 American Chemical Society |
| First Published: | First published in Journal of Medicinal Chemistry 66(13): 8951-8974 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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