Recent developments in adenosine A2A receptor ligands.

The development of potent and selective agonists and antagonists of adenosine receptors (ARs) has been a target of medicinal chemistry research for several decades, and recently the US Food and Drug Administration has approved Lexiscan, an adenosine derivative substituted at the 2 position, for use as a pharmacologic stress agent in radionuclide myocardial perfusion imaging. Currently, some other adenosine A(2A) receptor (A(2A)AR) agonists and antagonists are undergoing preclinical testing and clinical trials. While agonists are potent antiinflammatory agents also showing hypotensive effects, antagonists are being developed for the treatment of Parkinson's disease.However, since there are still major problems in this field, including side effects, low brain penetration (for the targeting of CNS diseases), short half-life, or lack of in vivo effects, the design and development of new AR ligands is a hot research topic.This review presents an update on the medicinal chemistry of A(2A)AR agonists and antagonists, and stresses the strong need for more selective ligands at the human A(2A)AR subtype, in particular in the case of agonists.