8-AZAXANTHINE DERIVATIVES AS ANTAGONISTS OF ADENOSINE RECEPTORS

A series of 1,3-dimethyl- and 1,3-dipropyl-8-azaxanthines, substituted at the N-8 or N-7 position with substituents which usually increase t he affinity of the xanthines for the adenosine receptors, was synthesi zed and studied in radioligand binding experiments. The substitution o f CH with N at the 8-position of both theophylline and caffeine dramat ically reduced the affinity, as demonstrated by the fact that 8-azathe ophylline and 8-azacaffeine were inert. The introduction of a methyl g roup at 8-position of 8-azatheophylline restored the antagonistic acti vity at A(2) receptors, while a 8-cycloalkyl substituent increased the affinity for both receptor subtypes. A more favorable effect on affin ity was produced by the substitution of the 7-methyl group in 8-azacaf feine with cycloalkyl groups. 7-Cyclopentyl-1,3-dimethyl-8-azaxanthine was 3 times more potent than caffeine at A(1) receptors and 6 times l ess active at A(2) receptors. On the contrary, the 7-cyclohexyl-1,3-di methyl-8-azaxanthine was more potent than caffeine at A(2) receptors. The substitution of 1- and 3-methyl groups with propyl in both 7- and 8-substituted 8-azatheophylline increased remarkably the affinity for A(1) receptors. The 7-cyclopentyl-1,3-dipropyl-8-azaxanthine appears t o be one of the most potent and selective among 7-alkyl-substituted xa nthines at A(1) receptors so far known. Because the 8-aza analogues of 8-substituted 1,3-dialkylxanthine were in any case less active than t he corresponding xanthine derivatives, it was confirmed that the hydro gen atom at the 7-position of xanthines plays an important role in the binding to adenosine receptors.