Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by a general dysfunction of the nervous system with a loss of nigrostriatal dopaminergic neurons. The primary nAChR populations in the nigrostriatal pathway, a4�2, a6�2* and a7, appear to be important for nicotine-mediated reduction in levodopa-induced dyskinesias (LIDs) or abnormal involuntary movements (AIMs) in parkinsonian animal models. We synthesized a novel series of compounds targeting a4�2 and a6�2* nAChRs that bound with very high affinity, partial to full agonists, and were potent desensitizers at both High Sensitivity a4�2 and a6/a3�2�3. Members of the lead series demonstrated desirable in vitro potency and efficacy for dopamine release assays in rat striatal synaptosomes. The lead compound from this series was assessed in both levodopa-treated unilateral 6-hydroxydopamine lesioned rats and in the MPTP-lesioned nonhuman primate model of PD. This lead compound decreased AIMs or LIDs in both animal models, and is progressing toward clinical studies.

NNR therapeutics for Parkinson's disease

244th National Meeting (2012)

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