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

Abstract

Our previous work discovered that combining the appropriate 5′- and N 6 -substitution in adenosine derivatives leads to the highly selective human A 1 adenosine receptor (hA 1 AR) agonists or highly potent dual hA 1 AR agonists and hA 3 AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N 6 -substituted-5′-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The N 6 -(±)- endo -norbornyl derivative 12 was the most potent and selective at A 1 AR and effective as an analgesic in formalin test in mice, but none of the 5′-pyrazolyl series compounds showed a dual behavior at hA 1 and hA 3 AR. Molecular modeling studies rationalized the structure–activity relationships and the selectivity profiles of the new series of A 1 AR agonists. Interestingly, an unexpected inverted binding mode of the N 6 -tetrahydrofuranyl derivative 14 was hypothesized to explain its low affinity at A 1 AR.