Fluorosulfonyl-substituted xanthines as selective irreversible antagonists for the A(1)-adenosine receptor

J Med Chem. 2000 Dec 28;43(26):4973-80. doi: 10.1021/jm000181f.


FSCPX (1) has been reported to be a potent, selective, and irreversible antagonist for the A(1)-adenosine receptor (AR). To obtain an irreversible A(1)AR antagonist with potentially better stability and to further elucidate the effects of linker structure on the pharmacological characteristics, several new analogues were targeted in which the labile ester linkage of 1 was replaced by more stable functionalities. In particular, alkyl and amide linkers between the xanthine pharmacophore and the reactive 4-fluorosulfonylphenyl group were explored. The data showed that the chemical composition of the linker affects the affinity and apparent irreversible binding to the A(1)AR. Overall, compound 23b appeared to have the most advantageous characteristics as a potential irreversible ligand for the A(1)AR. These include relatively high affinity for the A(1)AR as compared to the A(2A)AR, concentration-dependent and selective apparent irreversible binding to the A(1)AR, and ease of removal of unbound ligand from biological membranes. These properties indicate that 23b has the potential to be a useful tool for further study of the structure and function of the A(1)AR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Line
  • Cricetinae
  • Ligands
  • Mesocricetus
  • Purinergic P1 Receptor Antagonists*
  • Radioligand Assay
  • Rats
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1 / metabolism
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis*
  • Xanthines / chemistry
  • Xanthines / metabolism
  • Xanthines / pharmacology


  • 8-cyclopentyl-3-(3-(4-fluorosulfonylbenzamido)propyl)-1-propylxanthine
  • Ligands
  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1
  • Xanthines