Exploring the 7-oxo-thiazolo[5,4-d]pyrimidine core for the design of new human adenosine A3 receptor antagonists. Synthesis, molecular modeling studies and pharmacological evaluation

Abstract A new series of 5-methyl-thiazolo[5,4-d]pyrimidine-7-ones bearing different substituents at position 2 (aryl, heteroaryl and arylamino groups) was synthesized and evaluated in radioligand binding assays to determine their affinities at the human (h) A 1 , A 2A , and A 3 adenosine receptors (ARs). Efficacy at the hA 2B and antagonism of selected ligands at the hA 3 were also assessed through cAMP experiments. Some of the new derivatives exhibited good to high hA 3 AR affinity and selectivity versus all the other AR subtypes. Compound 2-(4-chlorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidine-7-one 4 was found to be the most potent and selective ligand of the series ( K i hA 3  = 18 nM). Molecular docking studies of the reported derivatives were carried out to depict their hypothetical binding mode in our hA 3 receptor model.