D1 and Functionally Selective Dopamine Agonists as Neuroprotective Agents in Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that results in major motor disturbances due primarily to loss of midbrain dopamine neurons. The mainstream treatment has been dopaminergic replacement therapy aimed at symptomatic relief, with the gold standard drug being the dopamine precursor levodopa. The general dogma has been that levodopa works primarily by indirectly activating the D2 family of dopamine receptors. Recently, a number of direct dopamine agonists that target the D2 and D3 dopamine receptors have been used as dopaminergic replacement strategies. Although these direct D2 and D3 drugs cause only modest improvement in motor function compared to levodopa, they can delay the initiation of levodopa and can act synergistically with levodopa. In addition, they can delay the onset of levodopa-related motor complications. Recent imaging data also suggest that they may have neuroprotective effects. Whereas D2/D3 agonists have received much attention as several drugs are available for clinical trials and usage, there has been a large body of data showing that the D1 receptor actually may play a larger role in restoration of normal motor function. This review examines the current use of dopamine D2/D3 agonists in treatment of PD and their potential for providing neuroprotection. Furthermore, we also examine the potential that D1 agonists might have in neuroprotective actions in the disease progression.