1-alkyl-8-(piperazine-1-sulfonyl)phenylxanthines: development and characterization of adenosine A2B receptor antagonists and a new radioligand with subnanomolar affinity and subtype specificity

J Med Chem. 2009 Jul 9;52(13):3994-4006. doi: 10.1021/jm900413e.


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 A(1) and A(2A) and the human A(3) receptors up to a concentration of 10 microM. 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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Drug Design
  • Humans
  • Kinetics
  • Ligands
  • Mice
  • Protein Binding
  • Radioligand Assay
  • Rats
  • Receptor, Adenosine A2B / metabolism
  • Xanthines / chemical synthesis
  • Xanthines / chemistry*
  • Xanthines / pharmacology


  • Adenosine A2 Receptor Antagonists
  • Ligands
  • Receptor, Adenosine A2B
  • Xanthines