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

Citation
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
Citations number
38
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
40
Issue
12
Year of publication
1997
Pages
1773 - 1778
Database
ISI
SICI code
0022-2623(1997)40:12<1773:SABEOT>2.0.ZU;2-Y
Abstract
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.