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Translating A_2A antagonist KW6002 from animal models to parkinsonian patients

From the Experimental Therapeutics Branch (Drs. Chase, Bibbiani, Bara-Jimenez, and Dimitrova), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; and the Psychology Department (Dr. Oh-Lee), Central Michigan University, Mount Pleasant, MI.

Address correspondence and reprint requests to Dr. T.N. Chase, Experimental Therapeutic Branch, Building 10, Room 5C103, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892-1406.

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A_2A antagonist for use in the management of Parkinson’s disease (PD) illustrates approaches to some of the relevant issues. Adenosine A_2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A_2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent L-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal -amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A_2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose L-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose L-dopa with fewer dyskinesias than produced by optimal-dose L-dopa alone. KW6002 also safely prolonged the efficacy half-time of L-dopa. The results suggest that drugs capable of selectively blocking adenosine A_2A receptors could confer therapeutic benefit to L-dopa–treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.

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