Targeting adenosine receptors with coumarins: synthesis and binding activities of amide and carbamate derivatives.

Objectives: With the aim of finding the structural features governing binding activity and selectivity against adenosine receptors (ARs), several 3-subtituted coumarins with amide (compounds 3-6) and carbamate (7-9) functions were synthesized. To study its possible influence on the binding activity and selectivity, a hydroxyl substituent was also introduced at position 4 of the coumarin moiety.
Methods: A new series of coumarins (3-9) were synthesized and evaluated by radioligand binding studies towards ARs.
Key Findings: None of the 4-hydroxy derivatives (4, 8 and 9) showed binding affinity for any of the ARs. None of the compounds interacted with the hA(2B) AR (K(i) > 100,000 nM). Compounds 3, 5, 6 and 7 had different activity profiles with dissimilar binding affinity and selectivity towards human A₁, A(2A) and A₃ ARs.
Conclusions:  The most remarkable derivative is compound 7, which presents the best affinity and selectivity for the A₃ adenosine receptor (K(i) = 5500 nM).
(© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.)