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Monoamine oxidase B inhibition and neuroprotection

Studies on selective adenosine A_2A receptor antagonists

From the Department of Chemistry (Drs. Castagnoli, Petzer, and Van der Schyf, S. Steyn and K. Castagnoli), Virginia Polytechnic Institute and State University, Blacksburg, VA; and Department of Neurology (Drs. Chen and Schwarzschild), Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Address correspondence and reprint requests to Dr. Neal Castagnoli, Jr., Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0212; e-mail: ncastagn{at}vt.edu

The principal therapeutic agents used in the management of Parkinson’s disease (PD) enhance nigrostriatal dopaminergic flux through either replenishment of depleted dopamine stores or the action of dopaminergic agonists. Adenosine A_2A receptor antagonists (e.g., KW–6002) may provide symptomatic relief in PD and perhaps also may display neuroprotective properties based on studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of nigrostriatal neurodegeneration. A second class of compounds that is neuroprotective in the MPTP model comprises inhibitors of the outer mitochondrial flavoenzyme monoamine oxidase B (MAO B), one of the two forms of MAO that regulate levels of brain neurotransmitter substances, including dopamine. In this article, data are presented that document the overlapping A_2A antagonist and MAO B inhibitory properties of several 2-styrylxanthinyl derivatives. A limited structure–activity analysis of these compounds and structurally related analogs is provided. The results raise the possibility that a single structure may offer the combined benefits of two pharmacologic strategies, each with symptomatic and potential neuroprotective benefits, for the management of PD.