| Abstract
| - “Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1−14).Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3ARwere determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a highratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typicallyshowed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reducerelative A3AR efficacy. Thus, several 5‘-OH derivatives appeared to be selective A3AR antagonists, i.e., 10,with 260-fold binding selectivity in comparison to the A1AR and displaying a characteristic docking modein an A3AR model. The corresponding 5‘-ethyluronamide analogues generally showed increased A3AR affinityand behaved as full agonists, i.e., 17, with 910-fold A3/A1 selectivity. Thus, N6-substituted 2-(1,2,3-triazolyl)adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A3AR antagonists,partial agonists, and agonists.
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