8-Azaxanthine derivatives as antagonists of adenosine receptors

J Med Chem. 1994 Sep 2;37(18):2970-5. doi: 10.1021/jm00044a018.


A series of 1,3-dimethyl- and 1,3-dipropyl-8-azaxanthines, substituted at the N8 or N7 position with substituents which usually increase the affinity of the xanthines for the adenosine receptors, was synthesized and studied in radioligand binding experiments. The substitution of CH with N at the 8-position of both theophylline and caffeine dramatically reduced the affinity, as demonstrated by the fact that 8-azatheophylline and 8-azacaffeine were inert. The introduction of a methyl group at 8-position of 8-azatheophylline restored the antagonistic activity at A2 receptors, while a 8-cycloalkyl substituent increased the affinity for both receptor subtypes. A more favorable effect on affinity was produced by the substitution of the 7-methyl group in 8-azacaffeine with cycloalkyl groups. 7-Cyclopentyl-1,3-dimethyl-8-azaxanthine was 3 times more potent than caffeine at A1 receptors and 6 times less active at A2 receptors. On the contrary, the 7-cyclohexyl-1,3-dimethyl-8-azaxanthine was more potent than caffeine at A2 receptors. The substitution of 1- and 3-methyl groups with propyl in both 7- and 8-substituted 8-azatheophylline increased remarkably the affinity for A1 receptors. The 7-cyclopentyl-1,3-dipropyl-8-azaxanthine appears to be one of the most potent and selective among 7-alkyl-substituted xanthines at A1 receptors so far known. Because the 8-aza analogues of 8-substituted 1,3-dialkylxanthine were in any case less active than the corresponding xanthine derivatives, it was confirmed that the hydrogen atom at the 7-position of xanthines plays an important role in the binding to adenosine receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Cattle
  • In Vitro Techniques
  • Purinergic P1 Receptor Antagonists*
  • Radioligand Assay
  • Receptors, Purinergic P1 / metabolism
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis*
  • Xanthines / metabolism
  • Xanthines / pharmacology


  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1
  • Xanthines
  • 8-azaxanthine