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Structural determinants of affinity of N 6 -substituted-5'-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N 6 -cycloalkyl and 3-halobenzyl groups furnished potent dual acting A 1 AR agonists and A 3 AR antagonists. 4 was the most potent dual acting human (h) A 1 AR agonist (K i = 0.45 nM) and A 3 AR antagonist (K i = 0.31 nM) and highly selective versus A 2A ; 11 and 26 were most potent at both h and rat (r) A 3 AR. All N 6 -substituted-5'-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hA 3 AR but agonists at the rA 3 AR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (A 3 AR antagonist blocked and A 3 AR agonist strongly potentiated). N 6 -Methyl-5'-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining A 1 AR and A 3 AR agonists. This study demonstrated for the first time the advantages of a single molecule activating two AR pathways both leading to benefit in this acute pain model.

journal of medicinal chemistry

Exploring the Role of N6-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice