8-Aryl- and 8-Cycloalkyl-1,3-dipropylxanthines: Further Potent and Selective Antagonists for A₁-Adenosine Receptors

A series of 1,3-dipropylxanthines were prepared with a variety of substituents at the 8-position. These included 8-aryl and 8-cycloalkyl groups. Polar carboxylate and carboxamide moieties’ were introduced as aryl substituents to increase water solubility. 1,3-Dipropyl-8-[2-hydroxy-4-[(carboxymethyl)oxy]phenyl]xanthine provided a functionalized congener with high potency (K_i= 37 nM) and selectivity (54-fold) for A₁-adenosine receptors. This congener was used for preparation of a series of other analogues, some with higher potency and some with higher selectivity. 8-Cyclopentyl- and 8-cyclohexyl-1,3-dipropylxanthines were both very potent (K_i= 1-1.5 nM) and selective for A₁receptors, while 8-cycloalkylmethyl analogues were 10-fold less potent, but still very selective for A₁receptors. 8-Piperidinyl and 8-pyrazinyl analogues had very low activities as adenosine receptor antagonists.