Allosteric Modulation of Adenosine A_2A Receptors as a New Therapeutic Avenue

The therapeutic potential of targeting adenosine A_2A receptors (A_2ARs) is immense due to their broad expression in the body and central nervous system. The role of A_2ARs in cardiovascular function, inflammation, sleep/wake behaviors, cognition, and other primary nervous system functions has been extensively studied. Numerous A_2AR agonist and antagonist molecules are reported, many of which are currently in clinical trials or have already been approved for treatment. Allosteric modulators can selectively elicit a physiologic response only where and when the orthosteric ligand is released, which reduces the risk of an adverse effect resulting from A_2AR activation. Thus, these allosteric modulators have a potential therapeutic advantage over classical agonist and antagonist molecules. This review focuses on the recent developments regarding allosteric A_2AR modulation, which is a promising area for future pharmaceutical research because the list of existing allosteric A_2AR modulators and their physiologic effects is still short.