Synthesis and biological evaluation of sugar-modified truncated carbanucleosides as A2A and A3 adenosine receptor ligands to explore conformational effect to the receptors

[Display omitted] •A series of C2-hexynyl truncated carbanucleosides were synthesized.•The North and South conformers were compared based on the conformational differences.•The study revealed that A2AAR and A3AR preferentially bind to the North conformation.•The North conformer (6a) exhibited the highest binding affinity to both receptors.•Docking studies identified steric clashes limiting the binding of South conformers. This study investigated the impact of conformation on the binding affinity of carbanucleosides to A2A and A3 adenosine receptors (ARs). A series of nucleosides, including saturated, unsaturated, North (N)-methano, and South (S)-methanocarbanucleosides was prepared, and their binding affinities to A2AAR and A3AR were assessed. Biological evaluations revealed that all synthesized (S)-methanocarbanucleosides had negligible binding to both receptors, and most (N)-methanocarbanucleosides exhibited high binding affinities. Molecular docking analysis showed that the (N)-methanocarbanucleoside 6a exhibited favorable interactions and minimal steric clashes in both A2AAR and A3AR. Conversely, the (S)-methanocarbanucleoside 7a appears to encounter significant steric clashes, which impeded its binding to A2AAR. Furthermore, when adopting the South conformation 7a was unable to bind to A3AR. Expanding upon the (N)-methanocarba moiety, various C8-aromatic groups were introduced to convert A2AAR agonists into antagonists and these modified compounds also exhibited strong binding affinity. These results suggest that the North conformation is favored by both A2AAR and A3AR, and that (N)-methanocarbanucleosides can serve as versatile structural moieties for dual targeting of A2AAR and A3AR. These findings offer promising avenues for the development of dual ligands for therapeutic applications in obesity and immunotherapy.