Abstract
A new series of 4′-selenoadenosine-5′-N,N-dimethyluronamide derivatives as highly potent and selective human A3 adenosine receptor (hA3AR) antagonists, is described. The highly selective A3AR agonists, 4′-selenoadenosine-5′-N-methyluronamides were successfully converted into selective antagonists by adding a second N-methyl group to the 5′-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA3AR. Among the synthesized compounds, 2-H-N6-3-iodobenzylamine derivative 9f exhibited the highest binding affinity at hA3AR. (Ki = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-N6-3-iodobenzylamine derivative 9l demonstrated hA3AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA3AR activation.
Highlights
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Adenosine, which is the endogenous ligand of the adenosine receptors (ARs), is an important neuromodulator and mediates through activation of its four receptors, consisting of A1, A2A, A2B, and A3 subtypes
All final compounds exhibited medium to high binding affinity toward A3 AR with high selectivity compared to other subtypes
Summary
Academic Editors: Catia Lambertucci and Rosaria VolpiniReceived: 23 March 2021Accepted: 9 April 2021Published: 14 April 2021Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Licensee MDPI, Basel, Switzerland.Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).Adenosine, which is the endogenous ligand of the adenosine receptors (ARs), is an important neuromodulator and mediates through activation of its four receptors, consisting of A1 , A2A , A2B , and A3 subtypes. These receptors are widely distributed in tissues and involved in various physiological activities [1]. Each subtype couples to a preferred type of
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