Development of Bicyclo[3.1.0]hexane-based A3 receptor ligands: closing the gaps in the structure–affinity relationships

Lemmerhirt, J.P.; Isaak, A.; Liu, R.; Kock, M.; Daniliuc, C.G.; Jacobson, K.A.; ... ; Junker, A. (2022)

Article / Letter to editor

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.

• Adenosine Receptors
• Methanocarba
• Bicyclo[3.1.0]hexane
• A3 Receptors

• All authors: Lemmerhirt, J.P.; Isaak, A.; Liu, R.; Kock, M.; Daniliuc, C.G.; Jacobson, K.A.; Heitman, L.H.; Junker, A.
• Date: 2022-03-31
• Journal: Molecules
• Volume: 27
• Issue: 7
• DOI: doi:10.3390/molecules27072283