History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents.

Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.