Synthesis and structure-activity relationships of 3,7-dimethyl-1-propargylxanthine derivatives, A2A-selective adenosine receptor antagonists

J Med Chem. 1997 Dec 19;40(26):4396-405. doi: 10.1021/jm970515+.


A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A2A adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A1 and A2A and compared with standard A2A adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A2A adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, Ki A2A = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, Ki A2A = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (Ki A2A = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A2A adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A2A affinity and/or selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Caffeine / metabolism
  • Molecular Structure
  • Phenethylamines / metabolism
  • Protein Binding
  • Purinergic P1 Receptor Antagonists*
  • Rats
  • Receptors, Purinergic P1 / metabolism
  • Structure-Activity Relationship
  • Theobromine / analogs & derivatives*
  • Theobromine / chemical synthesis
  • Theobromine / chemistry
  • Theobromine / metabolism
  • Theobromine / pharmacology
  • Xanthines / metabolism


  • Phenethylamines
  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1
  • Xanthines
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • KF 17837
  • N(6)-cyclohexyladenosine
  • Caffeine
  • 3,7-dimethyl-1-propargylxanthine
  • Adenosine
  • Theobromine