Treatment of Parkinson's disease (PD) has traditionally focused on dopamine replacement strategies such as LDOPA. While generally effective early on, L-DOPA has often proven inadequate for long term treatment due to serious adverse side effects. Recent studies in Dr. Conn's laboratory suggest that activators of metabotropic glutamate receptor mGluR4 may provide a novel pharmacological approach to the treatment of PD by targeting the indirect pathway of the basal ganglia. Furthermore, Dr. Conn and coworkers have developed a novel approach to activation of mGluR4 by development of allosteric potentiators that do not activate this receptor directly but dramatically potentiate the response to glutamate. While these studies provide an exciting proof of principle for a novel approach to activation of mGluR4, there is a need to develop novel compounds that have a higher potency and are useful for further in vivo studies. The goal of this work is to develop novel potent and selective allosteric potentiators of mGluR4. A threefold approach will be implemented, beginning with performing a high throughput screen mining for compounds that potentiate the glutamate response of mGluR4. In parallel with the HTS, medicinal chemistry studies will be pursued to improve upon the properties of known potentiators. Finally, mutagenesis studies will be performed to develop a better understanding of the molecular interactions involved in potentiator binding which will subsequently aid in the design of future compounds. Together these approaches will result in the development of novel small molecules that have a therapeutic effect on PD by reducing transmission through the indirect pathway. Furthermore, these studies will be complemented by ongoing electrophysiology and behavioral studies in Dr. Conn's laboratory that will determine the effects of these compounds in vitro models of basal ganglia function. ? ?
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