Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson's Disease

Background Treatment of motor fluctuations in Parkinson's disease ( PD ) remains an unmet challenge. Adenosine 2A (A 2A ) receptors are located along the indirect pathway and represent a potential target to enhance l ‐3,4‐dihydroxyphenylalanine ( l ‐ DOPA ) antiparkinsonian action. Methods This article summarizes the preclinical and clinical literature on A 2A antagonists in PD , with a specific focus on their effect on off time, on time, and dyskinesia. Findings Several A 2A receptor antagonists have been tested in preclinical studies and clinical trials. In preclinical studies, A 2A antagonists enhanced l ‐ DOPA antiparkinsonian action without exacerbating dyskinesia, but A 2A antagonists were generally administered in combination with a subthreshold dose of l ‐ DOPA , which is different to the paradigms used in clinical trials, where A 2A antagonists were usually added to an optimal antiparkinsonian regimen. In clinical settings, A 2A antagonists generally reduced duration of off time, by as much as 25% in some studies. The effect of on time duration is less clear, and in a few studies an exacerbation of dyskinesia was reported. Two A 2A antagonists have been tested in phase III settings: istradefylline and preladenant. Istradefylline was effective in two phase III trials, but ineffective in another; the drug has been commercially available in Japan since 2013. In contrast, preladenant was ineffective in a phase III trial and the drug was discontinued. A phase III study with tozadenant will begin in 2015; the drug was effective at reducing off time in a phase II b study. Other A 2A antagonists are in development at the preclinical and early clinical levels.