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

Cosimelli, Barbara; Greco, Giovanni; Laneri, Sonia; Novellino, Ettore; Sacchi, Antonia; Trincavelli, Maria Letizia; Giacomelli, Chiara; Taliani, Sabrina; Da Settimo, Federico; Martini, Claudia

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 μ m) 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 μ m, 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.

ADENOSINES; NUCLEOSIDES; G protein coupled receptors; ADENYLATE cyclase; PHOSPHOLIPASES

Chemical Biology & Drug Design, 2016, Vol 88, Issue 5, p724

1747-0277

Academic Journal

10.1111/cbdd.12801