Semirational Design of (North)-Methanocarba Nucleosides as Dual Acting A1 and A3 Adenosine Receptor Agonists:  Novel Prototypes for Cardioprotection

Ring-constrained adenosine analogues have been designed to act as dual agonists at tissue-protective A1 and A3 adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5‘-uronamides consistently lost affinity at A1/A2AARs and gained at A3AR. Among 9-riboside derivatives, only N 6-cyclopentyl and 7-norbornyl moieties were extrapolated for mixed A1/A3 selectivity and rat/human A3AR equipotency. Consequently, 2 was balanced in affinity and potency at A1/A3ARs as envisioned and dramatically protected in an intact heart model of global ischemia and reperfusion.