Development of Bicyclo[3.1.0]hexane-Based A<sub>3</sub> Receptor Ligands: Closing the Gaps in the Structure–Affinity Relationships
Jan Phillip Lemmerhirt,
Andreas Isaak,
Rongfang Liu,
Max Kock,
Constantin G. Daniliuc,
Kenneth A. Jacobson,
Laura H. Heitman,
Anna Junker
Affiliations
Jan Phillip Lemmerhirt
European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
Andreas Isaak
European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
Rongfang Liu
Leiden Academic Centre for Drug Research (LACDR), Division of Medicinal Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
Max Kock
European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
Constantin G. Daniliuc
Organisch-Chemisches Institut, University of Münster, Corrensstraße 40, 48149 Münster, Germany
Kenneth A. Jacobson
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Laura H. Heitman
Leiden Academic Centre for Drug Research (LACDR), Division of Medicinal Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
Anna Junker
European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
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.
