1-Alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: Development and Characterization of Adenosine A_2B 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_2B adenosine receptors. A_2B 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 (24, PSB-09120, K_i (human A_2B) = 0.157 nM) and 8-(4-(4-(4-chlorobenzyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (17, PSB-0788, K_i (human A_2B) = 0.393 nM). Moreover, 8-(4-(4-(4-chlorophenyl)piperazine-1-sulfonyl)phenyl)-1-propylxanthine (35, PSB-603) was developed as an A_2B-specific antagonist exhibiting a K_i value of 0.553 nM at the human A_2B receptor and virtually no affinity for the human and rat A₁ and A_2A and the human A₃ 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_2B receptors (K_D human A_2B 0.403 nM, mouse A_2B 0.351 nM).