Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A₃ Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary

Distinguishing compounds’ agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (K_i = 2.40 nM) as a potent human A₃ adenosine receptor (hA₃AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA₃AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor–ligand complex, the results indicated that the hydrogen bonding with Thr94^3.36 and His272^7.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds’ actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.