Development and Characterization of Potent Succinate Receptor Fluorescent Tracers
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Development and Characterization of Potent Succinate Receptor Fluorescent Tracers. / Ciba, Marija; Dibnah, Bethany; Hudson, Brian D.; Rexen Ulven, Elisabeth.
I: Journal of Medicinal Chemistry, Bind 66, Nr. 13, 2023, s. 8951–8974.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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