The primary motor deficits of Parkinson's disease are effectively improved by administration of the dopamine precursor L-dihydroxyphenylalanine, or levodopa. For unknown reasons, levodopa loses effectiveness after repeated administration, and becomes increasingly associated with the appearance of abnormal motor movements called dyskinesias. Medications effective in reducing the incidence and severity of dyskinesias induced by chronic levodopa treatment are currently lacking. Therefore, adjunct treatments that can effectively promote beneficial levodopa responses and/or reduce the severity of abnormal motor activity elicited by long-term levodopa exposure would be particularly valuable. Recent studies in animals and humans support the idea that blockade of certain classes of serotonin (5-HT) receptors in the brain reduces the severity of dyskinetic behavior elicited by L-DOPA treatment.
Intra-Cellular Therapies Inc. (ITI) is developing a novel class of compounds that block activity of 5-HT-2A receptors. We plan to evaluate these novel compounds for their ability to ameliorate levodopa-induced dyskinesias in a well-characterized animal model of PD. These studies will provide critical efficacy data necessary to test the therapeutic potential of a novel class of serotonin receptor antagonists as treatments for levodopa-induced dyskinesia in PD.
Final Outcome
A significant portion of this project focused on determining the drugability of the compounds, which are serotonin 5-HT2A receptor antagonists with activity as dopamine protein phosphorylation modulators (DPPMs). The drugs were tested for pharmacokinetics, brain penetration, and toxicity. Initial studies in pre-clinical models of dyskinesia showed some efficacy of these molecules in treating LDOPA-induced dyskinesia. Based on these and other studies, the lead compound has been advanced into human clinical safety testing, where it has been shown to be safe and well-tolerated in healthy volunteers.
Researchers
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Gretchen Snyder, PhD