Development of Bicyclo[3.1.0]hexane-Based A Receptor Ligands: Closing the Gaps in the Structure-Affinity Relationships.

The adenosine A receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at 1-, 2-, and 6-positions of the purine ring and variations of the 5'-position at the bicyclo[3.1.0]hexane moiety, closing existing gaps in the structure-affinity relationships. The most potent derivative displayed moderate AAR affinity (K of 0.38 μM) and high AR selectivity. A subset of compounds varied at 5'-position was further evaluated in functional P2YR assays, displaying no off-target activity.