Medicinal Chemistry of A3 Adenosine Receptor Modulators: Pharmacological Activities and Therapeutic Implications

It is well-known that the clinical use of exogenous adenosine is limited because it does not possess AR specificity and is rapidly metabolized by adenosine deaminase. Thus, instead of using adenosine, the synthetic chemical approaches have been concentrated toward the development of receptor-specific adenosine agonists or antagonists. All the pharmacological evidence found in the adenosine research field led to the design of thousands of compounds, few of which are now in clinical trials for treating different pathologies, with the aim to identify new leads potentially useful as novel diagnostic and therapeutic agents. It has been indeed well described that A3ARs play an important role in different human pathologies, suggesting the potential use of selective agonists and/or antagonists acting through AR modulation. The chemical development of several classes of hA3AR selective agonists and/or antagonists has permitted the identification of clinical candidates with an important impact on the drug discovery process.A3ARs could represent a possible target for pharmacological intervention to prevent different pathologies in both the central nervous system and the cardiovascular system, in inflammatory diseases, and in cancer.