An Overview of Adenosine A2A Receptor Antagonists in Parkinson's Disease

Adenosine A(2A) receptor antagonists represent a new way forward in the symptomatic treatment of Parkinson's disease (PD) through a non-dopaminergic mechanism. As a class, adenosine A(2A) antagonists are effective in reversing motor deficits in haloperidol-treated rodents, 6-OHDA-lesioned rats, and MPTP-treated primates when combined with low doses of L-dopa or dopamine agonist drugs. Importantly, they improve motor function without worsening dyskinesia and they may prevent the onset of involuntary movements. Adenosine A(2A) receptor antagonists are active in animal models of reduced cognition, anxiety, and depression and so this drug class may also be effective in controlling the neuropsychiatric components of nonmotor symptoms in PD. Preclinical evidence has shown that A(2A) antagonists can prevent neuronal loss in experimental models of PD and their disease modifying activity needs to be explored in man. Importantly, a number of A(2A) antagonists have been studied in PD in clinical trial for their effects on motor function. So far, little evidence has emerged of an effect of monotherapy with adenosine antagonists in early PD. However, in later stage, patient populations already treated with dopaminergic drugs but exhibiting "wearing off," adenosine antagonists have been demonstrated to reduce "off" time without increasing troublesome dyskinesia in phase IIB trials. However, in larger phase III evaluations, a consistent significant decrease in "off" time has proved more difficult to demonstrate-due in part to trial conduct. So far, only istradefylline has completed phase III development and it is now marketed for the treatment of PD. Adenosine A(2A) antagonists are the first non-dopaminergic approach to the treatment of PD to appear in the recent era. They represent a novel way of approaching therapy that will provide additional benefit to that achieved with dopaminergic medication, while avoiding common side effects and may in addition, improve some non-motor symptoms of PD that are currently poorly treated.