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Pharmacokinetics and Cognitive Side Effects of the Antidyskinetic Drug Fenobam in MPTP-treated Pre-clinical Models

This grant builds upon the research from a prior grant: A Novel Prodrug of Acamprosate for Treatment of L-DOPA-Induced Dyskinesias

Promising Outcomes of Original Grant:
The goal of our original project was to determine if a prodrug of acamprosate could inhibit levodopa-induced dyskinesias (LIDs) in a pre-clinical model. During the course of our studies we also investigated the effects of fenobam, another drug that modulates glutamate transmission. Fenobam showed remarkable antidyskinetic efficacy, reducing LIDs by more than 70% without interfering with the antiparkinsonian effect of levodopa treatment. The overall goal of the present work is to take advantage of this observed efficacy and to further develop fenobam as a treatment for LIDs.

Objectives for Supplemental Investigation:
Fenobam was studied in humans as a treatment for anxiety in the early 1980s and more recently as a treatment for Fragile X syndrome. Previous clinical experience with fenobam could accelerate its introduction into the clinic as a treatment for LIDs. The present research is directed at two important issues that need to be addressed before moving forward. First, we will assess the relationship between dose, plasma concentration, and efficacy of fenobam as a treatment for LIDs. The results of these studies will define the dose-response efficacy of fenobam and identify whether fenobam absorption is predictable enough for further development or whether a “prodrug” strategy will be needed to optimize delivery of fenobam. Second, we will determine the cognitive/behavioral side effects of fenobam in a pre-clinical model and define whether efficacious doses of fenobam are likely to produce cognitive effects in clinical models.

Importance of This Research for the Development of a New PD Therapy
These studies have a high probability of identifying a clear-cut pathway forward for this program, either by (1) leading directly to clinical trials of fenobam as a treatment for LIDs or (2) indicating the need for the development of a prodrug of fenobam to improve the PK characteristics and bioavailability of this compound.


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