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D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

By Richard B. Mailman, Yang Yang, Xuemei Huang

Posted 20 Sep 2020
bioRxiv DOI: 10.1101/2020.09.20.305375

Levodopa is the Parkinson’s disease standard-of-care, 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. Although there are consistent data in both primate models and in Parkinson’s disease showing that selective high intrinsic activity D1 agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 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 D2 antagonist remoxipride. These data provide evidence that selective D1 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 D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinson’s patients. ### Competing Interest Statement Dr. Mailman is an inventor of D1 agonist technology, the conflicts-of-interest of which are managed by the Pennsylvania State University College of Medicine. He is the past recipient of research funds and consulting compensation from Pfizer, Inc. Dr. Huang is an inventor of D1 agonist-related technology whose interests were assigned to the University of North Carolina. Dr. Huang has also received nominal transportation and per diem expenses from Acadia, Medtronics, and Cerevel Therapeutics, and research support from Pfizer, Biogen, and Biohaven. Drs. Mailman and Huang have no other conflicting interests. Dr. Yang has no conflicting interests. The opinions in this review are those of the authors alone and do not reflect those of the university or any other party.

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