Synthesis and structure-activity relationships of deazaxanthines: analogs of potent A1- and A2-adenosine receptor antagonists

J Med Chem. 1994 May 13;37(10):1526-34. doi: 10.1021/jm00036a019.


A set of 22 9-deazaxanthines (pyrrolo[3,2-d]pyrimidine-2,4-diones) and three 7-deazaxanthines (pyrrolo[2,3-d]pyrimidine-2,4-diones) with various substituents in the 1-, 3-, 7- or 9-, and 8-positions was synthesized and investigated in A1 and A2a adenosine receptor binding assays at rat brain cortical membranes and rat brain striatal membranes, respectively. 9-Deazaxanthines showed structure-activity relationships that were similar to those of xanthines. They were about equipotent to the corresponding xanthines at A2a adenosine receptors. 9-Deazaxanthines were generally at least 2-3-fold more potent than xanthines at A1 receptors and therefore exhibited higher A1 selectivities compared to the xanthines. 1,3-Dimethyl-8-(2-naphthyl)-9- deazaxanthine (19e) showed high affinity (Ki = 26 nM) and selectivity for A1 adenosine receptors. A hydroxyl function at N7 of 9-deazaxanthines was unfavorable for A1 and A2a receptor binding. 7-Deazaxanthines were considerably less potent compared to xanthines and to 9-deazaxanthines at both receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • In Vitro Techniques
  • Purinergic P1 Receptor Antagonists*
  • Rats
  • Receptors, Purinergic P1 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis
  • Xanthines / chemistry*
  • Xanthines / pharmacology*


  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1
  • Xanthines