Traditional therapies for treatment of Parkinson's disease (PD) based on dopamine replacement strategies eventually fail in most patients due to serious adverse effects and loss of efficacy with disease progression. Because of this, a great deal of effort has been focused on developing a detailed understanding of the circuitry and function of the basal ganglia in hopes of developing novel therapeutic approaches for restoring normal basal ganglia function in patients suffering from PD. Exciting advances in our understanding of the function of metabotropic glutamate receptors (mGluRs) and the distribution of mGluR subtypes in the basal ganglia suggest that members of this receptor family could serve as targets for novel therapeutic agents that would be effective in treatment of PD. We have performed a number of studies that suggest that the mGlu4 receptor subtype may be particularly attractive as a novel target for treatment of PD. mGlu4 is localized on presynaptic terminals in the synapse between the striatum an the globus pallidus (the striato-pallidal synapse). This is a critical synapse in the basal ganglia motor circuit and previous studies suggest that reduction of transmission at this synapse could have a therapeutic effect in PD patients. We have shown that activation of mGlu4 reduces transmission at the striato-GP synapse. Furthermore, we present data suggesting that agonists of mGlu4 may have an antiparkinsonian effect in several rodent models of PD. While these results are encouraging, it has been extremely difficult to develop selective agonists with high affinity for specific mGlu receptor subtypes that also have appropriate drug-like properties. We have exciting preliminary studies that provide a novel approach to developing small molecules that activate mGlu4. We have discovered a novel compound termed PHCCC that does not activate mGlu4 directly but dramatically potentiates activation of the receptor by glutamate or L-AP4. Furthermore, our preliminary studies suggest that allosteric potentiator of mGlu4 may have antiparkinsonian actions similar to those observed with traditional mGlu4 agonists. In the proposed studies we will rigorously test the hypothesis that mGlu4 is localized on critical striatal terminals and that activation of this receptor selectively reduces transmission at the Striatopallidal synapse. Furthermore, we will test the hypothesis that agonists or allosteric potentiators of this receptor can provide palliative relief in rodent models of PD by actions in the GP.
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