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

This study investigated the impact of conformation on the binding affinity of carbanucleosides to A and A adenosine receptors (ARs). A series of nucleosides, including saturated, unsaturated, North (N)-methano, and South (S)-methanocarbanucleosides was prepared, and their binding affinities to AAR and AAR 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 AAR and AAR. Conversely, the (S)-methanocarbanucleoside 7a appears to encounter significant steric clashes, which impeded its binding to AAR. Furthermore, when adopting the South conformation 7a was unable to bind to AAR. Expanding upon the (N)-methanocarba moiety, various C8-aromatic groups were introduced to convert AAR agonists into antagonists and these modified compounds also exhibited strong binding affinity. These results suggest that the North conformation is favored by both AAR and AAR, and that (N)-methanocarbanucleosides can serve as versatile structural moieties for dual targeting of AAR and AAR. These findings offer promising avenues for the development of dual ligands for therapeutic applications in obesity and immunotherapy.