Adenosine A2A Receptor Antagonists: Chemistry, SARs, and Therapeutic Potential

Many physiological processes are modulated by the naturally occurred nucleoside adenosine after interaction with four G-protein-coupled receptor subtypes named A1, A2A, A2B, and A3. All adenosine receptors are widely distributed in the body. The A2A subtype is present in the central nervous system in the dopamine-rich regions, in glutamatergic and GABAergic pathways intrinsic to the hippocampus, and in the cortex, where it is also co-expressed with dopamine D2 and cannabinoid CB1 receptors. The A2A adenosine receptor distribution also regards numerous peripheral tissues such as blood vessels, endothelial, lymphoid, smooth muscle cells, and neurons. Since it is an emerging receptor implicated in many pathologies and its blockade could be beneficial in neuroinflammation, neurodegenerative disorders, and cancer, this review focuses the attention on the chemical structures of selective A2A adenosine receptor antagonists, divided into different chemical classes. One section is dedicated to the representation of published crystallographic structures and molecular modeling studies. Furthermore, the use of A2A adenosine receptor antagonists for the treatment of neurodegenerative disorders, as well as their potential as neuroprotective agents, will be discussed. Finally, due to the involvement of the A2A adenosine receptor in activated immune cells, it will be taken into consideration the potential application of A2A adenosine receptor antagonists in the anti-cancer therapy.