1-Alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: Development and Characterization of Adenosine A<sub>2B</sub> Receptor Antagonists and a New Radioligand with Subnanomolar Affinity and Subtype Specificity

A new series of 1-alkyl-8-(piperazine-1-sulfonyl)phenylxanthines was designed, synthesized, and characterized in radioligand binding and functional assays at A<sub>2B</sub> adenosine receptors. A<sub>2B</sub> antagonists with subnanomolar affinity and high selectivity were discovered. The most potent compounds were 1-ethyl-8-(4-(4-(4-trifluoromethylbenzyl)piperazine-1-sulfonyl)phenyl)xanthine (<b>24</b>, PSB-09120, <i>K</i><sub>i</sub> (human A<sub>2B</sub>) = 0.157 nM) and 8-(4-(4-(4-chlorobenzyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (<b>17</b>, PSB-0788, <i>K</i><sub>i</sub> (human A<sub>2B</sub>) = 0.393 nM). Moreover, 8-(4-(4-(4-chlorophenyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (<b>35</b>, PSB-603) was developed as an A<sub>2B</sub>-specific antagonist exhibiting a <i>K</i><sub>i</sub> value of 0.553 nM at the human A<sub>2B</sub> receptor and virtually no affinity for the human and rat A<sub>1</sub> and A<sub>2A</sub> and the human A<sub>3</sub> receptors up to a concentration of 10 μM. A tritiated form of the compound was prepared as a new radioligand and characterized in kinetic, saturation, and competition studies. It was shown to be a useful pharmacological tool for the selective labeling of human as well as rodent A<sub>2B</sub> receptors (<i>K</i><sub>D</sub> human A<sub>2B</sub> 0.403 nM, mouse A<sub>2B</sub> 0.351 nM).