Abstract
Levodopa is the standard-of-care for Parkinson's disease, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches the efficacy of levodopa. There are consistent data in both primate models and in Parkinson's disease showing that selective high intrinsic activity D(1) agonists can equal levodopa in efficacy. There are, however, no data on whether such compounds would be effective in severe disease when levodopa efficacy is low or absent. We compared two approved antiparkinson drugs (levodopa and the D(2/3) agonist bromocriptine) with the experimental selective D(1) full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernible improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D(1) agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D(2) antagonist remoxipride. These data provide evidence that selective D(1) agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D(1) agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson's patients.