Synthesis and Biological Evaluation of the Enantiomers of the Potent and Selective A₁-Adenosine Antagonist 1,3-Dipropyl-8-[2-(5,6-epoxynorbonyl)]- xanthine

Abstract

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.

Characterization of the A2BAdenosine Receptor from Mouse, Rabbit, and Dog

“…Thus, these compounds are not particularly useful for discriminating A 1 or A 2A versus A 2B AR-mediated responses. Two other compounds that are preferable for selectively inhibiting A 1 ARs include the 8-bicyclo xanthine antagonist BG 9719 and, in particular, the adenine antagonist N-0861; both are potent A 1 AR antagonists (K i ϳ1 nM) (Shryock et al, 1992;Pfister et al, 1997) that are 700 to 1000-fold and Ͼ15,000-fold selective versus A 2B ARs, respectively. The results of our binding data also confirm that MRS 1523 displays low binding potency for A 2B ARs, ensuring that this compound is unlikely to nonspecifically inhibit A 2B ARs, even at high concentrations required to inhibit A 3 ARs.…”

Comparison of Three Different A1Adenosine Receptor Antagonists on Infarct Size and Multiple Cycle Ischemic Preconditioning in Anesthetized Dogs

“…BG 9719 (1,3-dipropyl-8-[2-(5,6-epoxy-s-norbornyl)]xanthine; previously named CVT-124) is one of the most potent and se-lective A 1 AR antagonists developed to date (Belardinelli et al, 1995;Pfister et al, 1997). It is a xanthine derivative containing a norbornyl ring at the C-8 position ( Fig.…”

“…It is a xanthine derivative containing a norbornyl ring at the C-8 position ( Fig. 1) that effectively increases A 1 AR affinity while decreasing potency at A 2A ARs (Belardinelli et al, 1995;Pfister et al, 1997). The affinities of BG 9719 for rat and human A 1 ARs are 0.67 and 0.45 nM (Pfister et al, 1997), respectively, with selectivity versus A 2A ARs of 1800-fold (rat) and 2400-fold (human).…”

“…1) that effectively increases A 1 AR affinity while decreasing potency at A 2A ARs (Belardinelli et al, 1995;Pfister et al, 1997). The affinities of BG 9719 for rat and human A 1 ARs are 0.67 and 0.45 nM (Pfister et al, 1997), respectively, with selectivity versus A 2A ARs of 1800-fold (rat) and 2400-fold (human). In human patients with congestive heart failure, acute administration of BG 9719 increased urine output without decreasing GFR (Gottlieb et al, 2000).…”

Adenosine A1Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency

“…The other A 1 AdoR antagonist was BG-9719, which is more than 1,800-fold selective for the A 1 AdoR in rats and more than 2,400-fold in humans. 11,12 BG-9719 has a duration of effect of about 30-60 minutes.…”