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Chem Biol Drug Des. 2016 Nov;88(5):724-729. doi: 10.1111/cbdd.12801. Epub 2016 Jul 11.

4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives as novel non-nucleoside agonists for the adenosine A1 receptor.

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Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.


Three 4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives (4-6) were investigated as potential non-nucleoside agonists at human adenosine receptors (ARs). When tested in competition binding experiments, these compounds exhibited low micromolar affinity (Ki values comprised between 1.2 and 1.9 μm) for the A1 AR and no appreciable affinity for the A2A and A3 ARs. Evaluation of their efficacy profiles by measurement of intracellular cAMP levels revealed that 4 and 5 behave as non-nucleoside agonists of the A1 AR with EC50 values of 0.47 and 0.87 μm, respectively. No clear concentration-response curves could be instead obtained for 6, probably because this compound modulates one or more additional targets, thus masking the putative effects exerted by its activation of A1 AR. The three compounds were not able to modulate A2B AR-mediated cAMP accumulation induced by the non-selective AR agonist NECA, thus demonstrating no affinity toward this receptor.


4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives; A1 AR agonists; A1 AR efficacy; A1 AR ligands; A1 adenosine receptor; non-nucleoside adenosine receptor agonists

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