O Future Directions

The Parkinson's-Reversing Breakthrough

Parkinson Disease Manual

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DA has long been linked with PD and schizophrenia in a unique and multifaceted relationship. Although this close association ensures that DA and the dopaminergic systems will remain a primary focus for the treatment of both PD and schizophrenia, other avenues of therapy are on the horizon. A focus on neuroprotective agents for the treatment of PD may provide a more efficacious approach than DA symptomology-based therapies. Such treatments would target the mechanisms involved in the pathogenesis of the disease. A promising antioxidant, coenzyme Q10 (ubiquinone), has been proposed to slow down functional decline.136 Based on findings that mitochondrial dysregulation and oxidative damage may play a role in the loss of nigral neurons, it is hypothesized that coenzyme Q10 could be an effective neuroprotectant.136,137 Inhibitors of glutamate, anti-inflammatory, and antiapoptotic drugs have also been proposed as PD neuroprotectants,138,139 although currently there is a lack of clinical verification. Yet, another approach is the use of gene therapy, using a glial cell line-derived neurotrophic factor to slow neurodegeneration in PD.18,140,141 New approaches are also being explored in terms of schizophrenia treatment. Over the past decade, a dysfunction of glutaminergic neurons has been suggested to contribute to the pathophysiology of schizophrenia. This theory is supported by the fact that a noncompetitive inhibitor at NMDA receptors (a subtype of glutamate receptors) produces positive and negative symptoms of schizophrenia in normal subjects. Compounds that target the NMDA receptor may offer an alternative treatment for schizophrenia.142 Ultimately, future strategies for the pharmacological treatment of PD and schizophrenia will likely evolve into a combination DA and non-DA approaches, appropriately tailored to each patients needs.

review questions

1. Using chlorpromazine as the prototype, discuss the SAR of the phenothiazine antipsychotics.

2. Ropinirole and rotigotine act as agonists at D3 receptors. Compare the structures of these two compounds with that of DA. Clearly specify the pharmacophoric groups in ropinirole and rotigotine that impart D3 agonist activity.

3. Shown below is the structure of the typical antipsychotic trifluoperazine. Give the structure of five likely metabolites for this compound.

4. Explain the rationale for the combination product levo-dopa/carbidopa/entacapone in the treatment of PD.

5. Shown on the next column are the structures of the atypical antipsychotics olanzapine and clozapine. Describe the pharmacological action of these compounds at the D2 and 5-HT2A receptors. What is the relationship between the circled phenyl ring in clozapine and the 2-methylthio-phene ring in olanzapine?

Chapter 13 # Central Dopaminergic Signaling Agents 489 CH3 CH3

Chapter 13 # Central Dopaminergic Signaling Agents 489 CH3 CH3

Clozapine" Olanzapine

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