Dual actions of A(2A) adenosine receptor antagonists on motor dysfunction and neurodegenerative processes

Of the four known adenosine receptors, the A(2A) receptor has received much attention over the last few years. The discovery of high-affinity and sele ctive A(2A) adenosine receptor antagonists, together with the development o f different genetic lines of mice lacking A(2A) receptors, have greatly con tributed to the new insights into the mechanisms whereby A(2A) receptors mo dulate central nervous system functions. Efforts made using the prototypic A(2A) receptor antagonists, e.g., the 8-styrylxanthine KW 6002 and the pyra zolotriazolopyrimidine SCH 58261, have shown that these drugs are effective in different models of motor impairment mimicking the main features of Par kinson's disease. Moreover, these drugs show neuroprotective properties in models of brain injury. Consistent with pharmacology, A(2A) receptor knocko ut mice have been found to be less sensitive to both motor impairment and n eurochemical changes relevant to neurodegenerative disorders. The main effe ct of A(2A) receptor blockade or inactivation is related to selective inter action with dopamine-mediated function in the striatum. However, there are responses which appear to be independent of dopamine receptors while the me chanisms underlying neuroprotection remain to be elucidated. Overall, there are now compounds that appear to be promising for treatment of Parkinson's disease and related neurodegenerative disorders. The efforts currently ong oing to understand their efficacy in patients will make it possible to asse ss whether A(2A) receptor blockers are a new interesting class of antiparki nsonian agents. Drug Dev. Res. 52:379-386, 2001. (C) 2001 Wiley-Liss, Inc.