mGluR4 PAM

The metabotropic glutamate receptor 4 (mGluR4) belongs to the Group III mGluRs (Class C GPCR) and is negatively coupled to adenylate cyclase via activation of the Gαi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in transmitter release from presynaptic terminals.

mGluR4 is currently receiving much attention based primarily upon its unique distribution and the recent evidence that activation of this receptor plays key modulatory role in many CNS and non-CNS pathways.

mGluR4 PAM is emerging as a promising target for the treatment of motor (and non-motor) symptoms as well as a disease-modifying agent in Parkinson’s disease through a non-dopaminergic approach.

Symptoms of Parkinson’s disease (PD) are believed to be due to progressive death of dopaminergic neurons that originate from the substantia nigra, pars compacta and project into the striatum (Figure 1). Reduction in dopaminergic neurotransmission leads to an imbalance in the direct and indirect output pathways of the basal ganglia. Reduction of transmission at the inhibitory GABAergic striato-pallidal synapse in the indirect pathway is believed to result in alleviation of these symptoms. mGluR4 is abundant in striato-pallidal synapses.Its localization suggests it functions as a presynaptic heteroreceptor on GABAergic neurons, suggesting in turn that selective activation or positive modulation of mGluR4 would decrease GABA release in this synapse, thereby decreasing output of the indirect pathway and reducing or eliminating the PD symptoms. 

Addex has discovered a novel, nanomolar, selective, brain penetrant and orally bioavailable mGluR4 PAM, ADX88178, and demonstrated its efficacy in several different rodent models of PD. ADX88178 reverses haloperidol induced catalepsy (HIC) in rats at 3 and 10 mg/kg after oral administration. More importantly, the combination of ADX88178 (3, 10 and 30 mg/Kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats. In addition, co-administration of ADX88178 (10 mg/kg, p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent with an L-DOPA sparing action that may prove to be therapeutically useful for the management of motor symptoms of PD.

The search for novel drugs that relieve motor symptoms of Parkinsonism whist attenuating the ongoing degeneration of nigrostriatal neurons is of particular interest. Orthosteric mGluR4 agonist L-AP4 has demonstrated neuroprotective effects in a 6-OHDA rodent model of PD and first positive allosteric  modulator (-)-PHCCC reduced nigrostriatal degeneration in mice treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). Those studies provide preclinical evidence suggesting that mGluR4 activators constitute a strong approach not only for symptomatic treatments of PD, but also potentially as disease modifiers.

Anxiety disorders are among the most prevalent psychiatric disorders in the world, and are co-morbid with Parkinson’s disease. Excessive glutamatergic neurotransmission is one important feature of anxiety pathophysiology. Based on presynaptic localization of mGluR4 in brain areas involved in anxiety and mood disorders, and dampening excessive brain excitability, the mGluR4 activators may represent a new generation of anxiolytic therapeutics.

ADX88178 was shown to be active in two preclinical rodent models of anxiety: the marble burying test in mice and EPM in mice and rats. ADX88178 also displayed an anxiolytic-like profile in the rat EPM test (minimum effective dose of 10 mg/kg) after oral dosing. More importantly, target engagement was proven using mGluR4 knockout mice in the EPM test, which completely abolished the effect of ADX88178 (10 mg/kg, p.o.) in those mice. 

During the progression of the disease, degeneration of DA neurons in the SNc leads to a reduction of nigrostriatal neurotransmission causing an imbalance between the direct/indirect pathways, via D1 and D2 receptors respectively. mGluR4 is expressed at the striatopallidal synapses and STN-SNr synapses. mGluR4 activators restore balance by decreasing GABA and glutamate neurotransmitter tone, demonstrated by improvement of motor function in acute and chronic preclinical models. (Gpe, external segment of globus pallidus; STN, subthalamic nucleus; SNr substantia nigra pars reticulata; SNc, substantia nigra pars compacta; Thal: Thalamus).