? ? 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 mGluR4 receptor subtype may be particularly attractive as a novel target for treatment of PD. We have shown that activation of mGluR4 reduces transmission at the synapse between the striatum and 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 provide a therapeutic benefit to PD patients. Consistent with this, we found that agonists of mGluR4 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 mGluR subtypes that also have appropriate drug-like properties. We have exciting preliminary studies that provide a novel approach to developing small molecules that activate mGluR4. We have discovered a novel compound termed PHCCC that does not activate mGluR4 directly but dramatically potentiates activation of the receptor by glutamate or L-AP4. Furthermore, our preliminary studies suggest that an allosteric potentiator of mGluR4 has antiparkinsonian actions similar to those observed with traditional mGluR4 agonists. In the proposed studies we will screen a library of >150,000 compounds that were selected based on maximal diversity and chemical properties for novel molecules that act as allosteric potentiators of mGluR4. In addition, we will perform a series of rigorous secondary and tertiary assays will be performed to determine selectivity, potency, and cytotoxicity of hits from the primary screen. This high throughput screen will provide the basis for future studies aimed at developing allosteric potentiators of mGluR4 that are suitable for clinical testing. ? ?
| Iderberg, Hanna; Maslava, Natallia; Thompson, Analisa D et al. (2015) Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist. Neuropharmacology 95:121-9 |
| Niswender, Colleen M; Johnson, Kari A; Weaver, C David et al. (2008) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol 74:1345-58 |
| Niswender, Colleen M; Johnson, Kari A; Luo, Qingwei et al. (2008) A novel assay of Gi/o-linked G protein-coupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors. Mol Pharmacol 73:1213-24 |
