Selective A3 Adenosine Receptor Antagonist Radioligand for Humanand Rodent Species

The A3 adenosine receptor (A3AR) is a target forpain, ischemia, and inflammatory disease therapy. Among theligand tools available are selective agonists and antagonists,including radioligands, but most high-affinity non-nucleosideantagonists are limited in selectivity to primate species. We haveexplored the structure-activity relationship of a previouslyreported A3AR antagonist DPTN9(N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide) for radiolabeling, in-cluding 3-halo derivatives (3-iodo, MRS7907), and characterized9as a high -affinity radioligand [3H]MRS7799. A3ARKdvalues were(nM): 0.55 (human), 3.74 (mouse), and 2.80 (rat). An extendedmethyl acrylate (MRS8074,19) maintained higher affinity (18.9 nM) than a 3-((5-chlorothiophen-2-yl)ethynyl) derivative20.Compound9had an excellent brain distribution in rats (brain/plasma ratio similar to 1). Receptor docking predicted its orthosteric sitebinding by engaging residues that were previously found to be essential for AR binding. Thus the new radioligand promises to be auseful species-general antagonist tracer for receptor characterization and drug discovery

Automated summary

The structure-activity relationship of an A3AR antagonist has been explored and a high-affinity radioligand has been developed, which shows promise as a useful tool for receptor characterization and drug discovery.