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4‐amino‐6‐alkyloxy‐2‐alkylthiopyrimidine derivatives as novel non‐nucleoside agonists for the adenosine A 1 receptor
Author(s) -
Cosimelli Barbara,
Greco Giovanni,
Laneri Sonia,
Novellino Ettore,
Sacchi Antonia,
Trincavelli Maria Letizia,
Giacomelli Chiara,
Taliani Sabrina,
Da Settimo Federico,
Martini Claudia
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12801
Subject(s) - nucleoside , adenosine , chemistry , agonist , adenosine receptor , intracellular , stereochemistry , intrinsic activity , ec50 , receptor , biochemistry , in vitro
Three 4‐amino‐6‐alkyloxy‐2‐alkylthiopyrimidine derivatives ( 4 – 6 ) were investigated as potential non‐nucleoside agonists at human adenosine receptors ( AR s). When tested in competition binding experiments, these compounds exhibited low micromolar affinity ( K i values comprised between 1.2 and 1.9 μ m ) for the A 1 AR and no appreciable affinity for the A 2A and A 3 AR s. Evaluation of their efficacy profiles by measurement of intracellular cAMP levels revealed that 4 and 5 behave as non‐nucleoside agonists of the A 1 AR with EC 50 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 A 1 AR . The three compounds were not able to modulate A 2B AR ‐mediated cAMP accumulation induced by the non‐selective AR agonist NECA , thus demonstrating no affinity toward this receptor.