1,8-disubstituted xanthine derivatives:: Synthesis of potent A2B-selective adenosine receptor antagonists

3-Unsubstituted xanthine derivatives bearing a cyclopentyl or a phenyl residue in the 8-position were synthesized and developed as A(2)B adenosine receptor antagonists. Compounds bearing polar substituents were prepared to obtain water-soluble derivatives. 1-Alkyl-8-phenylxanthine derivatives were found to exhibit high affinity for A(2B) adenosine receptors (ARs). 1,8-Disubstituted xanthine derivatives were equipotent to or more potent than 1,3,8-trisubstituted xanthines at A(2B) ARs, but generally less potent at A(1) and A(2A), and much less potent at A(3) ARs. Thus, the new compounds exhibited increased A2B selectivity versus all other AR subtypes. 9-Deazaxanthines (pyrrolo[2,3-d]pyrimidindiones) appeared to be less potent at A(2B) ARs than the corresponding xanthine derivatives. 1-Propyl-8-p-sulfophenylxanthiiie (17) was the most selective compound of the present series, exhibiting a K-i value of 53 nM at human A(2B) ARs and showing greater than 180-fold selectivity versus human A, ARs. Compound 17 was also highly selective versus rat A, ARs (41-fold) and versus the other human AR subtypes (A(2A) > 400-fold and A3 > 180-fold). The compound is highly water-soluble due to its sulfonate function. 1-Butyl-8-p-carboxyphenylxanthine (10), another polar analogue bearing a carboxylate function, exhibited a K-i value of 24 nM for A(2B) ARs, 49-fold selectivity versus human and 20-fold selectivity versus rat A, ARs, and greater than 150-fold selectivity versus human A2A and A3 ARs. 8-[4-(2-Hydroxyethylamino)-2-oxoethoxy)phenyl]-1-propylxanthine (29) and 1-butyl-8-[4(4-benzyl)piperazino-2-oxoethoxy)phenyl]xanthine (35) were among the most potent A(2B) antagonists showing K-i values at A(2B) ARs of 1 nM, 57-fold (29) and 94-fold (35) selectivity versus human A(1), ca. 30-fold selectivity versus rat A(1), and greater than 400-fold selectivity versus human A(2A) and A(3) ARs. The new potent, selective, water-soluble A(2B) antagonists may be useful research tools for investigating A(2B) receptor function.