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Two modes of tethering a chiral (phenylisopropyl)amino substituent in pyrazolo[3,4-d]pyrimidines and purines have been explored. One mode gave (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5- propoxy-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (12a) and its corresponding R-enantiomer 12b, which were selective for A2 and A1 adenosine receptors, respectively. The corresponding diimidazo[1,2-c:4',5'-e]pyrimidines 12e and 12f were analogously selective. This is the first example where a single chiral recognition unit provides enantiomers with opposite selectivities for adenosine receptors. The second mode gave (2S-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5- propoxy-3H-imidazo[1,2-c]-pyrazolo[4,3-e]pyrimidine (12c) and its corresponding R-enantiomer 12d. Compounds 12c and 12d were significantly less potent than 12a and 12b at A1 receptors, and were nonselective.

Several 8-substituted 1,3-dipropylxanthines were synthesized, and their receptor binding affinities at adenosine A1 and A2 receptors were measured. When enantiomeric pairs of compounds were examined, the R enantiomers were significantly more potent than the corresponding S enantiomers. The most potent compound at the A1 receptor was (R)-3,7-dihydro-8-(1-methyl-2-phenylethyl)-1,3-dipropyl-1H-purine-2,6-di one (5a; MDL 102,503), whose Ki value at the A1 receptor was 6.9 nM. However, a more selective compound was (R)-3,7-dihydro-8-(1-phenylpropyl)-1,3-dipropyl-1H-purine-2,6-dione (5d; MDL 102,234), which had a Ki value of 23.2 nM at the A1 receptor and an A2/A1 ratio of 153.

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