Structure-Based Design, Synthesis, and In Vivo Antinociceptive Effects of Selective A₁ Adenosine Receptor Agonists

Our previous work discovered that combining the appropriate 5'- and N⁶-substitution in adenosine derivatives leads to the highly selective human A₁ adenosine receptor (hA₁AR) agonists or highly potent dual hA₁AR agonists and hA₃AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N⁶-substituted-5'-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The N⁶-(±)-endo-norbornyl derivative 12 was the most potent and selective at A₁AR and effective as an analgesic in formalin test in mice, but none of the 5'-pyrazolyl series compounds showed a dual behavior at hA₁ and hA₃AR. Molecular modeling studies rationalized the structure-activity relationships and the selectivity profiles of the new series of A₁AR agonists. Interestingly, an unexpected inverted binding mode of the N⁶-tetrahydrofuranyl derivative 14 was hypothesized to explain its low affinity at A₁AR.