Neurotransmitters other than dopamine, such as norepinephrine, 
5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in 
Parkinson's disease (PD) and contribute to its symptomatology. Thus, the 
progress of non-dopaminergic therapies for PD has attracted much interest in 
recent years. Among new classes of drugs, adenosine A2A antagonists have emerged 
as promising candidates. The development of new highly selective adenosine A2A 
receptor antagonists, and their encouraging anti-parkinsonian responses in 
animal models of PD, has provided a rationale for clinical trials to evaluate 
the therapeutic potential and the safety of these agents in patients with PD. To 
date, the clinical research regarding A2A antagonists and their potential 
utilization in PD therapy continues to evolve between drugs just or previously 
discontinued (preladenant and vipadenant), new derivatives in development 
(tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug 
istradefylline, which has finally been licensed as an anti-parkinsonian drug in 
Japan. All these compounds have been shown to have a good safety profile and be 
well tolerated. Moreover, results from phase II and III trials also demonstrate 
that A2A antagonists are effective in reducing off-time, without worsening 
troublesome dyskinesia, and in increasing on-time with a mild increase of 
non-troublesome dyskinesia, in patients at an advanced stage of PD treated with 
L-DOPA. In addition, early findings suggest that A2A antagonists might also be 
efficacious as monotherapy in patients at an early stage of PD. This review 
summarizes pharmacological and clinical data available on istradefylline, 
tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.