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

Abstract

This study investigated the impact of conformation on the binding affinity of carbanucleosides to A_2A 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 A_2AAR 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 A_2AAR and A₃AR. Conversely, the (S)-methanocarbanucleoside 7a appears to encounter significant steric clashes, which impeded its binding to A_2AAR. 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 A_2AAR agonists into antagonists and these modified compounds also exhibited strong binding affinity. These results suggest that the North conformation is favored by both A_2AAR and A₃AR, and that (N)-methanocarbanucleosides can serve as versatile structural moieties for dual targeting of A_2AAR and A₃AR. These findings offer promising avenues for the development of dual ligands for therapeutic applications in obesity and immunotherapy.