Extended N6 Substitution of Rigid C2-Arylethynyl Nucleosides for Exploring the Role of Extracellular Loops in Ligand Recognition at the A3 Adenosine Receptor

摘要

2-Arylethynyl-(N)-methanocarba adenosine 5′-methyluronamides containing rigid N⁶-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A3 adenosine receptor (AR). Radioligand binding confirmed A3AR selectivity and N⁶-1S,2R stereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrained N⁶ groups was explored by docking to an A3AR homology model, indicating specific hydrophobic interactions with the second extracellular loop able to modulate the affinity profile. 2-Pyridylethynyl derivative >18 was administered orally in mice to reduce chronic neuropathic pain in the chronic constriction injury model.