INVESTIGATION INTO THE TOXICITY OF DOPAMINE THIOETHERS AND THE ANTI-INFLAMMATORY ACTIVITIES OF PULATIVE MAO-B INHIBITOR METABOLITES

Abstract

Parkinson’s disease (PD) is typically treated by increasing dopamine levels in the brain. In PD patients an increased generation of potentially toxic thioether metabolites of dopamine has been reported. However, information on the activities of these metabolites is scarce. We hypothesized that the different dopamine and DOPA thioether metabolites could be toxic to neurons. Thus, the major thioether metabolites of DA and DOPA were synthesized and tested for their toxicity in neuronal cultures. The results of this study may have implications on the rationale for dopamine-boosting therapies. MAO-B inhibitors are a well-established therapy in conjunction with DOPA. Previously, our lab has discovered a series of selective nanomolar monoamine oxidase B (MAO-B) inhibitors. These inhibitors have been shown to possess neuroprotective properties independent of MAO-B inhibition in animal models of Parkinson’s disease. We hypothesized that the metabolites of these inhibitors may possess anti-neuroinflammatory activities. The parent’s MAO-B inhibitory activity synergistically combined with its metabolites’ anti-neuroinflammatory activity could represent a novel concept in treating the complex pathoetiology of neurodegenerative diseases. Thus, several putative metabolites for the MAO-B inhibitors were synthesized and tested in a microglia cell-based assay.