Dual actions of A2A adenosine receptor antagonists on motor dysfunction and neurodegenerative processes

Abstract

Of the four known adenosine receptors, the A2A receptor has received much attention over the last few years. The discovery of high-affinity and selective A2A adenosine receptor antagonists, together with the development of different genetic lines of mice lacking A2A receptors, have greatly contributed to the new insights into the mechanisms whereby A2A receptors modulate central nervous system functions. Efforts made using the prototypic A2A receptor antagonists, e.g., the 8-styrylxanthine KW 6002 and the pyrazolotriazolopyrimidine SCH 58261, have shown that these drugs are effective in different models of motor impairment mimicking the main features of Parkinson's disease. Moreover, these drugs show neuroprotective properties in models of brain injury. Consistent with pharmacology, A2A receptor knockout mice have been found to be less sensitive to both motor impairment and neurochemical changes relevant to neurodegenerative disorders. The main effect of A2A receptor blockade or inactivation is related to selective interaction with dopamine-mediated function in the striatum. However, there are responses which appear to be independent of dopamine receptors while the mechanisms 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 ongoing to understand their efficacy in patients will make it possible to assess whether A2A receptor blockers are a new interesting class of antiparkinsonian agents. © 2001 Wiley-Liss, Inc.