mGluRs & parkinson's disease

mGluR5 inhibition (ADX48621 & ADX10059)
Preclinical research in rodents and primates shows that mGluR5 inhibition  alleviates levodopa induced dyskinesia in models of Parkinson’s disease. The preclinical evidence also suggests that mGluR5 inhibition may be  an effective dopamine sparing strategy.

mGluR5 is found in regions of the brain considered to be key control points in the neuronal movement circuits thought to be responsible for the abnormal signaling by the neurotransmitter glutamate. Perturbations in glutamate signaling (along with disruptions in dopaminergic signaling) is believed to be an underlying cause  of movement disorders like Parkinson's disease. As such, inhibiting mGluR5 could act to re-establish normal movement via a non-dopaminergic mechanism, thereby offering a dopamine sparing therapy.

Seperately, preclinical findings also suggest that mGlu5 receptor antagonist may be neuroprotective and may, therefore, hold potential to treat disease progression.


mGluR4 activation (mGluR4 PAM)
Published research shows that mGluR4 activators, like those in development in a collaboration between Addex and Merck & Co., Inc., could work via two distinct mechanisms to alleviate symptoms of Parkinson’s disease and, potentially, even slow the progression of the disease:

1) mGluR4 activation triggers a compensatory mechanism, mediated by glutamate, that may spare and/or potentiate the use of dopamine receptor activators; 2) mGluR4 activation may have neuroprotective effects that help preserve the brain’s dopaminergic neurons, thus delaying progression of the disease.

Merck has been a pioneer in research on mGluR receptors and the metabatropic glutamatergic system for multiple indications. For example, research by Merck scientists provided the first evidence that mGluR4 activation has potential for treatment of Parkinson’s disease. However, a remaining challenge was to make drug-like molecules that activated mGluR4 in a specific fashion. Addex is the leader in developing truly selective small molecule drug candidates targeting glutamate receptors and has discovered exquisitely selective mGluR4 positive allosteric modulators (PAMs).

Dopamine functions in the brain at the top of the basal ganglia motor circuit, which is composed of two pathways — the “direct” pathway and the “indirect” pathway — that regulate signaling to the thalamus via two brain regions in the basal ganglia system: the substantia nigra pars reticulate (SNr), and the internal globus pallidus (GPi). Both direct and indirect pathways target the thalamus via a non-dopaminergic mechanism (GABA signaling).

The direct and indirect pathways balance each other. The direct pathway exerts an inhibitory effect on SNr/GPi signaling, while the indirect pathway exerts an excitatory effect; both must operate in balance for the thalamus to allow normal motor function.

In Parkinson’s disease, dopaminergic neurons begin to die off for reasons unknown, causing a depletion of dopamine in the basal ganglia. This dopamine deficiency leads to an imbalance between the direct and indirect pathways. In the direct pathway, decreased dopamine leads to decreased inhibition of SNr/GPi signaling. In the indirect pathway, it causes an excess release of glutamate, resulting in increased excitation of the SNr/ GPi. The results of this imbalance is the improper motor function seen in Parkinson’s disease.

While most therapeutics attempt to restore balance to the system by increasing the amount of dopamine at the top of the circuit, Addex’ mGluR4 PAMs decrease glutamate release in the indirect pathway to reduce excitatory signals, effectively harmonizing the indirect pathway with the reduced inhibition of SNr/GPi signaling in the direct pathway.

The belief is that this rebalanced signaling will restore proper motor circuit function. Since mGluR4 modulators do not result in dopaminergic stimulation, patients could be spared the neurological side effects associated with dopamine-related therapies, such as the dyskinesia (involuntary movements) caused by levodopa. Avoiding dopaminergic stimulation also should sidestep problems with tolerance to long-term dopamine-related treatment.

parkinson's disease
ADX48621 in parkinson's disease
mGluR4 PAM in parkinson's disease