1,3,8-Trisubstituted Xanthines. Effects of Substitution Pattern upon Adenosine Receptor A₁/A₂ Affinity

A series of 11 8-substituted xanthines having three different substitution patterns on the 1- and 3-positions [pattern a (R₁ = R₃ = CH₂CH₂CH₃), b (R₁ = CH₂CH₂CH₃, R₃ = CH₃), and c (R₁ = CH₃, R₃ = CH₂CH₂CH₃)] was prepared. These compounds were assessed for affinity and selectivity in binding to adenosine A₁ and A₂ receptors. Compounds with greatest affinity at the A₁ receptor had the 1,3-substitution pattern a. With one exception, compounds with pattern a also exhibited the most potent binding at the A₂ receptor; however, several compounds with pattern c were equipotent at the A₂ receptor with those having pattern a. Additionally, the substituants on the 1- and 3-positions of these 8-substituted xanthines were equally important for determining maximum affinity to the A₁ receptor, while the substituent at the 3-position is more important than the substituent at the 1-position for potency at the A₂ receptor. As a result of this, it is possible to maximize selectivity for the A₁ receptor by choice of the 1- and 3-position substituents. However, the R₁/R₃ substitution pattern required for maximum A₁ selectivity is also dependent upon the substituent in the 8-position in a manner which is not fully understood.