A2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders

Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein-coupled receptors, and, to date, four subtypes have been characterized and named A(1), A(2A), A(2B), and A(3). In recent years, adenosine receptors, particularly the A(2A) subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson's and Alzheimer's diseases, multiple sclerosis, and neuropsychiatric conditions. In fact, it has been demonstrated that inhibition of A(2A) adenosine receptors exerts neuroprotective effects counteracting neuroinflammatory processes and astroglial and microglial activation. The A(2A) adenosine receptor antagonist istradefylline, developed by Kyowa Hakko Kirin Inc., was approved in Japan as adjunctive therapy for the treatment of Parkinson's disease, and very recently, it was also approved by the US Food and Drug Administration. These findings pave the way for new therapeutic opportunities, so, in this review, a summary of the most relevant and promising A(2A) adenosine receptor antagonists will be presented along with their preclinical and clinical studies in neuroinflammation related diseases.