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 (R 1 =R 3 =CH 2 CH 2 CH 3 ), b (R 1 =CH 2 CH 2 CH 3 , R 3 =CH 3 ) and c (R 1 =CH 3 , R 3 =CH 2 CH 2 CH 3 )] was prepared. These compounds were assessed for affinity and selectivity in binding to adenosine A 1 and A 2 receptors. Compounds with greatest affinity at the A 1 receptor had the 1,3-substitution pattern a. With one exception, compounds with pattern a also exhibited the most potent binding at the A 2 receptor; however, several compounds with pattern c were equipotent at the A 2 receptor with those having pattern a. Additionally, the substituents on the 1- and 3-positions of these 8-substituted xanthines were equally important for determining maximum affinity to the A 1 receptor, while the substituent at the 3-position is more important than the substituent at the 1-position for potency at the A 2 receptor. As a result of this, it is possible to maximize selectivity for the A 1 receptor by choice of the 1- and 3-position substituents. However, the R 1 /R 3 substitution pattern required for maximum A 1 selectivity is also dependent upon the substituent in the 8-position in a manner which is not fully understood