structure-based design, synthesis, and in vivo antinociceptive effects of selective a 1 adenosine receptor agonists

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 a1ar 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.