5′‑C‑Ethyl-tetrazolyl‑N⁶‑Substituted Adenosine and 2‑Chloro-adenosine Derivatives as Highly Potent Dual Acting A₁ Adenosine Receptor Agonists and A₃ Adenosine Receptor Antagonists

A series of N⁶-substituted-5′-C-(2-ethyl-2H-tetrazol-5-yl)-adenosine and 2-chloro-adenosine derivatives was synthesized as novel, highly potent dual acting hA₁AR agonists and hA₃AR antagonists, potentially useful in the treatment of glaucoma and other diseases. The best affinity and selectivity profiles were achieved by N⁶-substitution with a 2-fluoro-4-chloro-phenyl- or a methyl- group. Through an in silico receptor-driven approach, the molecular bases of the hA₁- and hA₃AR recognition and activation of this series of 5′-C-ethyl-tetrazolyl derivatives were explained.