mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease

Abstract

Although Parkinson's disease was first diagnosed nearly 200 years ago, its effective treatment still remains elusive for most of those diagnosed. The gold standard of treatment for most patients is 3,4-dihydroxy-L-phenylalanine. This drug works for most individuals early in the disease; however, resistant symptoms start to emerge after several years of treatment. There has been increased interest in finding novel therapies to help Parkinson's disease patients. Such strategies may have the benefit of not only treating the symptomatic issues of the disorder, but might also offer promise in protecting dopaminergic neurons from further degeneration. One such target that is now receiving much attention from the scientific community is the metabotropic glutamate receptor mGluR4. In this article, we briefly review Parkinson's disease and then recent work in the mGluR area, with a focus on the efforts being made toward finding and optimizing novel mGluR4 positive allosteric modulators (PAMs). Preclinically in rodent models, mGluR4 activation has offered much promise as a novel treatment of Parkinson's disease. Additionally, the specific use of PAMs, rather than direct-acting agonists at the orthosteric glutamate site, continues to be validated as a viable treatment option for this target. It is anticipated that continued progress in this area will further our understanding of the potential of mGluR4 modulation as a novel symptomatic and potentially disease-modifying treatment for Parkinson's disease.

Figure 1

Commonly used agents for dopamine-replacement therapy: 3,4-dihydroxy-L-phenylalanine (1), benserazide (2), bromocriptine (3), pergolide (4), ropinole (5), pramipexole (7), selegeline (8) and entacapone (9).

Figure 2. Simplified model of basal ganglia circuitry in normal physiology and Parkinson’s disease

Excitatory (glutamatergic) projections are shown by light arrows and inhibitory (GABAergic) projections are shown by dark arrows. (A) In the normal BG circuit, direct (striatum to GPi/SNr) and indirect (striatum to GPe) projections to the output nuclei are balanced by striatal dopaminergic tone. D1 receptor-containing neurons stimulate transmission through the direct pathway and D2 receptor-containing neurons inhibit transmission through the indirect pathway. These circuits converge at the GPi/SNr with a balance of inhibitory (via direct pathway) and excitatory (via indirect pathway) inputs to properly regulate inhibitory output to the thalamus. mGluR4 (circle) is localized at the synapse between the striatum and GPe (striatopallidal synapse) as well as synapses between the STN and SNc. (B) In the Parkinson’s BG circuit, the loss of striatal dopamine produces an imbalance in the direct and indirect pathways leading to too much inhibitory tone from the output nuclei. mGluR4-mediated decreases in GABA (striatopallidal synapse) and glutamate (STN–SNc synapse) release are hypothesized to restore balance to the output nuclei and possibly prevent further degeneration of SNc neurons via excitotoxic mechanisms. GPe: External segment of the globus pallidus; GPi: Internal segment of the globus pallidus; SNc: substantia nigra pars compacta; SNr: substantia nigra pars reticulata; STN: subthalamic nucleus. Modified from [21,22].

Figure 3

Glutamate (9), L-AP4 (10), L-SOP (11), APCD (12), APCT (13) and other phosphonate-containing group III mGluR agonists.

Figure 4

APCT-I (13).

Figure 5. PHCCC potentiates the effects of glutamate in cells expressing mGluR4

Cells were incubated with indicated concentrations of PHCCC prior to the addition of increasing concentrations of glutamate. PHCCC progressively shifts the potency of glutamate (EC₅₀) to the left by 1.7-fold (at 1 μM), 3.1-fold (at 3 μM), and 5.8-fold (at 10 μM). Data were independently generated for this review by CM Niswender using mGluR4-CHO cells as described in Niswender et al. [65]. DMSO: Dimethyl sulfoxide.

Figure 6

The mGluR4-positive allosteric modulator (–)-PHCCC (18) and the mGluR1 antagonist (–)-CPCCOEt (19).

Figure 7

Recently disclosed mGluR4-positive allosteric modulators from Vanderbilt University, TN, USA.

Figure 8

Recently disclosed mGluR4-positive allosteric modulators from Merck research laboratories.