Development of Bicyclo[3.1.0]hexane-Based A₃ Receptor Ligands: Closing the Gaps in the Structure–Affinity Relationships

Abstract

The adenosine A3 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 A3AR affinity (Ki of 0.38 μM) and high A3R selectivity. A subset of compounds varied at 5′-position was further evaluated in functional P2Y1R assays, displaying no off-target activity.

Keywords

• Adenosine receptors
• methanocarba
• bicyclo[3.1.0]hexane
• A₃ receptors