4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives as novel non-nucleoside agonists for the adenosine A1receptor.
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 (Kivalues comprised between 1.2 and 1.9 μm) for the A1AR and no appreciable affinity for the A2Aand A3ARs. Evaluation of their efficacy profiles by measurement of intracellular cAMP levels revealed that 4 and 5 behave as non-nucleoside agonists of the A1AR with EC50values 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 A1AR. The three compounds were not able to modulate A2BAR-mediated cAMP accumulation induced by the non-selective AR agonist NECA, thus demonstrating no affinity toward this receptor.
Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy. barbara.cosimelli@unina.it.
Barbara
0000-0002-3841-5389
B
Cosimelli
Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
Giovanni
G
Greco
Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
Sonia
S
Laneri
Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
Ettore
E
Novellino
Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
Antonia
A
Sacchi
Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.
Maria Letizia
ML
Trincavelli
Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.
Chiara
C
Giacomelli
Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.
Sabrina
S
Taliani
Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.
Federico
F
Da Settimo
Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.
Claudia
C
Martini
D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D058907:Adenosine A1 Receptor Agonists; D020033:Protein Isoforms; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D000242:Cyclic AMP; C030986:pyrimidine
4-amino-6-alkyloxy-2-alkylthiopyrimidine derivatives; A1 AR agonists; A1 AR efficacy; A1 AR ligands; A1 adenosine receptor; non-nucleoside adenosine receptor agonists