Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu_2/4 Heteromers

Abstract

Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu4 are coexpressed, whereas other compounds potentiate mGlu4 responses regardless of mGlu2 coexpression. We report here the discovery and characterization of VU0418506, a novel mGlu4 PAM with activity in rodent PD models. Using pharmacological approaches and Complemented Donor–Acceptor resonance energy transfer (CODA-RET) technology, we find that VU0418506 does not potentiate agonist-induced activity when mGlu2 and mGlu4 are heterodimerized, suggesting that the antiparkinsonian action of mGlu4 PAMs can be induced by compounds without activity at mGlu2/4 heteromers.

An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

“…Several compounds have displayed consistent limited activity in rodent models when given alone, but with the potential for l ‐dopa sparing (i.e., ability to preserve maximal antiparkinsonian motor benefit with reduction of l ‐dopa dosage) . Despite the validity of these rodent models, considering the compelling evidence that the function of mGlu receptors can be context dependent, evidence of mGlu4 PAM effectiveness in heterogeneous outbred primates (heterogeneity in genetic backgrounds, disease stage and history, sexes, and l ‐dopa dosage), with clinically relevant endpoints, has been eagerly awaited . The results of our study provide characterization of an mGlu4 PAM in primates and a demonstration of further potential than l ‐dopa‐sparing not only confirming, but also extending the results reported in rats.…”

“…At the corticostriatal synapses, mGlu4 decreases excitatory transmission from the cortex . The strong rationale for using mGlu4 as a therapeutic target in PD is further supported by preclinical evidence that shows that positive allosteric modulators (PAM) of mGlu4 reduce motor disability in rodent models of PD . Successful transition to clinical trials in PD requires a safe, brain‐penetrant, target‐specific drug with proven therapeutic efficacy in the MPTP‐lesioned macaque model …”

Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells

“…These receptors are strict dimers and have until recently only been considered as homodimers ( Romano et al, 1996 ; Kunishima et al, 2000 ). However, recent studies revealed the possible existence of heterodimeric mGluRs ( Doumazane et al, 2011 ; Kammermeier, 2012 ; Yin et al, 2014 ; Niswender et al, 2016 ), as observed with other class C GPCRs ( Marshall et al, 1999 ; Zhao et al, 2003 ; Pin and Bettler, 2016 ). The mGluRs constitute therefore an interesting model to tackle the issue of heterodimeric GPCRs in vivo.…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Recent studies suggest that mGlu 2 forms functional heterodimers with mGlu 4 that are expressed in the CNS and that some PAMs can selectively activate homomeric relative to heteromeric forms of the receptor (Figure 3; Kammermeier, 2012; Niswender et al, 2016; Yin et al, 2014). Interestingly some mGlu 4 PAMs have antipsychotic-like effects in rodent models (Kalinichev et al, 2014; Slawinska et al, 2013), including Lu AF21934, which acts as a robust PAM of mGlu 2/4 heterodimers (Niswender et al, 2016; Yin et al, 2014), raising the possibility that mGlu 2/4 heterodimers could play a key role in mediating the antipsychotic efficacy seen with mGlu 4 and mGlu 2 PAMs. Furthermore, mGlu 2 and mGlu 3 readily form mGlu 2 /mGlu 3 heterodimers in cell lines (Levitz et al, 2016) and these receptors are highly co-expressed in the PFC and other brain regions (Petralia et al, 1996).…”

“…However, at present, it is still unclear how allosteric modulators differentiate between these complexes. The mGlu 2/4 allosteric modulators outlined above appear to act at a conserved binding site on a single protomer (mGlu 2 or mGlu 4 ) of the mGlu 2/4 complex (Niswender et al, 2016). Future studies will be needed to fully understand why some modulators that bind at a single protomer modulate mGlu 2/4 signaling, whereas others do not.…”