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2-Triazole-Substituted Adenosines:  A New Class of Selective A3 Adenosine Receptor Agonists, Partial Agonists, and Antagonists

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journal contribution
posted on 14.12.2006, 00:00 by Liesbet Cosyn, Krishnan K. Palaniappan, Soo-Kyung Kim, Heng T. Duong, Zhan-Guo Gao, Kenneth A. Jacobson, Serge Van Calenbergh
“Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (114). Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative 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 mode in an A3AR model. The corresponding 5‘-ethyluronamide analogues generally showed increased A3AR affinity and 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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