Structure-based design, synthesis, and in vivo antinociceptive effects of selective A1 adenosine receptor agonists

Article abstract of DOI:10.1021/acs.jmedchem.7b01399

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.