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
Jr. Pfister et al., 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, Journal of medicinal chemistry, 40(12), 1997, pp. 1773-1778
The individual enantiomers 8 and 12 of the potent and highly selective
racemic A(1)-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorborn
yl)]xanthine (ENX, 4) were synthesized utilizing asymmetric Diels-Alde
r cycloadditions for the construction of the norbornane moieties. The
absolute configuration of 12 was determined by X-ray crystallography o
f the 4-bromobenzoate 14, which was derived from the bridged secondary
alcohol 13. The latter was obtained from 12 by an acid-catalyzed intr
amolecular rearrangement. The binding affinities of the enantiomers 8
and 12 and the racemate 4 at guinea pig, rat, and cloned human A(1)- a
nd A(2a)-adenosine receptor subtypes were determined. The S-enantiomer
12 (CVT-124) appears to be one of the more potent and clearly the mos
t 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. Bo
th enantiomers, administered intravenously to saline-loaded rats, indu
ced diuresis via antagonism of renal A(1)-adenosine receptors.