Parkinson's disease (PD) is the second most prevalent neurodegenerative 
disorder, affecting up to 10 million people worldwide. Current treatment 
primarily involves symptom management with dopaminergic replacement therapy. 
Levodopa remains the most effective oral treatment, although long-term use is 
associated with complications such as wearing off, dyskinesias, and on-off 
fluctuations. Non-dopaminergic medications that improve PD symptoms and motor 
fluctuations are in demand. Adenosine A2A receptors are abundantly expressed 
within the basal ganglia and offer a unique target to modify abnormal striatal 
signaling associated with PD. Preclinical animal models have shown the ability 
of adenosine A2A receptor antagonists to improve PD motor symptoms, reduce motor 
fluctuations and dyskinesia, as well as protect against toxin-induced neuronal 
degeneration. Both istradefylline and preladenant have demonstrated moderate 
efficacy in reducing off time in PD patients with motor fluctuations. The safety 
and efficacy of this class of compounds continues to be defined and future 
studies should focus on non-motor symptoms, dyskinesias, and neuroprotection.