Highlights on the development of A(2A) adenosine receptor agonists and antagonists.

Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.