Selective A3 Adenosine Receptor Antagonist Radioligand for Human and Rodent Species

The A3 adenosine receptor (A3AR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non-nucleoside antagonists are limited in selectivity to primate species. We have...

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Published in:ACS medicinal chemistry letters 2022-04, Vol.13 (4), p.623-631
Main Authors: Suresh, R. Rama, Gao, Zhan-Guo, Salmaso, Veronica, Chen, Eric, Campbell, Ryan G, Poe, Russell B, Liston, Theodore E, Jacobson, Kenneth A
Format: Article
Language:English
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Summary:The A3 adenosine receptor (A3AR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non-nucleoside antagonists are limited in selectivity to primate species. We have explored the structure–activity relationship of a previously reported A3AR antagonist DPTN 9 (N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]­nicotinamide) for radiolabeling, including 3-halo derivatives (3-iodo, MRS7907), and characterized 9 as a high -affinity radioligand [3H]­MRS7799. A3AR K d values were (nM): 0.55 (human), 3.74 (mouse), and 2.80 (rat). An extended methyl acrylate (MRS8074, 19) maintained higher affinity (18.9 nM) than a 3-((5-chlorothiophen-2-yl)­ethynyl) derivative 20. Compound 9 had an excellent brain distribution in rats (brain/plasma ratio ∼1). Receptor docking predicted its orthosteric site binding by engaging residues that were previously found to be essential for AR binding. Thus the new radioligand promises to be a useful species-general antagonist tracer for receptor characterization and drug discovery.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.1c00685