Adenosine receptor (AR) subtypes are involved in several physiological and pharmacological processes. Ligands that are able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on coumarin scaffold. Therefore, a series of 3-phenylcarboxamidocoumarins were synthesized and their affinity for the human AR subtypes was screened by radioligand binding assays for A(1), A(2A) and A(3) receptors and for A(2B) by adenylyl cyclase assay. Compound 26 was found to be the most remarkable, with a hA(1)/hA(3) and hA(2A)/hA(3) selectivity of 42, for the A(3) AR (K-i=2.4m). Receptor-driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound 26 and for the following optimization process. Moreover, compound 26 presents drug-like properties according to the general guidelines linked to the concept.