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New selective A(2A) agonists and A(3) antagonists for human adenosine receptors: synthesis, biological activity and molecular docking studies
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 8
2015 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 6, no 6, 1178-1185 p.Article in journal (Refereed) Published
Abstract [en]

We report the synthesis and pharmacological characterization of a new series of adenosine derivatives on the four adenosine receptors (ARs). In radioligand binding assays, some of the compounds (1, 4, 6 and (R)-6) display a potent affinity for the A(2A)AR (K-i values < 10 nM) with high A(1)/A(2A) and A(2B)/A(2A) selectivity, moderate for the A(3)AR and low for the A(1)AR. The affinity of the epimeric mixture 6 was similar to that of the corresponding (R)-6 stereoisomer and 10-fold higher than that of the (S)-6 stereoisomer. The phenylethylamino group appears to play a key role on the activity, but introduction of groups of different sizes and electronegativity does not induce a substantial change in affinity for the A(2A)AR. In functional assays, most of the compounds produced similar amounts of cAMP compared to NECA, thus behaving as full A(2A)AR agonists. In addition, compounds 1, 2, 3, 5, (S)-6 and 9 resulted to be good antagonists for A(3)AR with K-B in the 6-14 nM range. Docking studies on the A(2A)AR showed a conserved binding mode consistent with previous A(2A)AR agonist-bound crystal structures, allowing for a rational interpretation of the SAR of this compound series.

Place, publisher, year, edition, pages
2015. Vol. 6, no 6, 1178-1185 p.
National Category
Biological Sciences Basic Medicine
URN: urn:nbn:se:su:diva-119029DOI: 10.1039/c5md00086fISI: 000355985500022OAI: diva2:843050
Available from: 2015-07-24 Created: 2015-07-24 Last updated: 2015-07-24Bibliographically approved

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Rodriguez, David
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