Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbonyl)]-xanthine

J Med Chem. 1997 Jun 6;40(12):1773-8. doi: 10.1021/jm970013w.


The individual enantiomers 8 and 12 of the potent and highly selective racemic A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine (ENX, 4) were synthesized utilizing asymmetric Diels-Alder cycloadditions for the construction of the norbornane moieties. The absolute configuration of 12 was determined by X-ray crystallography of the 4-bromobenzoate 14, which was derived from the bridged secondary alcohol 13. The latter was obtained from 12 by an acid-catalyzed intramolecular rearrangement. The binding affinities of the enantiomers 8 and 12 and the racemate 4 at guinea pig, rat, and cloned human A1- and A2a-adenosine receptor subtypes were determined. The S-enantiomer 12 (CVT-124) appears to be one of the more potent and clearly the most A1-selective antagonist reported to date, with K1 values of 0.67 and 0.45 nM, respectively, at the rat and cloned human A1-receptors and with 1800-fold (rat) and 2400-fold (human) subtype selectivity. Both enantiomers, administered intravenously to saline-loaded rats, induced diuresis via antagonism of renal A1-adenosine receptors.

MeSH terms

  • Animals
  • Diuresis / drug effects
  • Guinea Pigs
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Purinergic P1 Receptor Antagonists*
  • Rats
  • Receptors, Purinergic P1 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis*
  • Xanthines / chemistry
  • Xanthines / metabolism
  • Xanthines / pharmacology


  • 1,3-dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine
  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1
  • Xanthines