New 2,6,9-trisubstituted adenines as adenosine receptor antagonists: a preliminary SAR profile

A new series of 2,6,9-trisubstituted adenines (5–14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A(1), A(2A) and A(3) adenosine receptors and in adenylyl cyclase experiments for their potency at the human A(2B) subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N(6) position of 9-propyladenine significantly increased binding affinity at the human A(1) and A(3) adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending on the receptor subtype and/or on the substituent present in the N(6) position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A(2A) subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human A(2B) subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct receptor selectivity profiles.