Adenosine Receptor Ligands, Probes, and Functional Conjugates: A 20-Year History of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidines (PTP)

Adenosine receptors are G protein-coupled receptors (GPCRs) involved in several processes in the human body. Their involvement in pathologies like coronary vasodilation, neurodegenerative diseases, inflammation, cancer, and pain make them interesting therapeutic targets. In particular, antagonism at the A2A and A3 adenosine receptor subtypes is of particular interest due to the central role in Parkinson’s disease and immunoncology of the first, and in cancer, glaucoma, and inflammation of the second. Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus is one of the most studied scaffolds to develop A2A and A3 adenosine receptor antagonists. In fact, a well distinct structure–activity relationship exists for these receptors. As a consequence, pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-based antagonists have also represented an optimal starting point to design probes and multifunction molecules that potently and selectively target A2A and A3 adenosine receptors. In this review, we reported the structure–activity relationship of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines at all the adenosine receptors along with all functionalization performed till now with their applications to study the structure and function of A3, but especially A2A adenosine receptors. Thus, pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and adenosine receptors are simply examples that would serve as a model that could be applied to every GPCR when a robust structure–activity relationship of a ligand class is known.