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

“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 A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomola...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-12, Vol.49 (25), p.7373-7383
Main Authors: Cosyn, Liesbet, Palaniappan, Krishnan K, Kim, Soo-Kyung, Duong, Heng T, Gao, Zhan-Guo, Jacobson, Kenneth A, Van Calenbergh, Serge
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - chemical synthesis
Adenosine - pharmacology
Adenosine A3 Receptor Agonists
Adenosine A3 Receptor Antagonists
Animals
Biological and medical sciences
CHO Cells
Cricetinae
Cricetulus
Cyclic AMP - biosynthesis
Humans
Medical sciences
Models, Molecular
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Radioligand Assay
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - pharmacology
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Summary:“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 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0608208