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

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 mGlu_2/4 heteromers.