Development of Bicyclo[3.1.0]hexane-Based A(3) Receptor Ligands: Closing the Gaps in the Structure–Affinity Relationships

The adenosine A(3) 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 30 displayed moderate A(3)AR affinity (Ki of 0.38 μM) and high A(3)R selectivity. A subset of compounds varied at 5′-position was further evaluated in functional P2Y(1)R assays, displaying no off-target activity.