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

The individual enantiomers 8 and 12 of the potent and highly selective racemic A(1)-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 A(1)- and A(2a)-adenosine receptor subtypes were determined. The S-enantiomer 12 (CVT-124) appears to be one of the more potent and clearly the most A(1)-selective antagonist reported to date, with K-i values of 0.67 and 0.45 nM, respectively, at the rat and cloned human A(1)-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 A(1)-adenosine receptors.