Identification of Positive Allosteric Modulators VU0155094 (ML397) and VU0422288 (ML396) Reveals New Insights into the Biology of Metabotropic Glutamate Receptor 7

Abstract

Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

“…1). This phenomenon referred to as "stimulus-bias" (although it has had many other monikers including "agonist-directed trafficking of receptor stimulus," "functional selectivity," and "biased agonism") has now been observed for many GPCRs, including mGlu 1 , mGlu 4 , mGlu 7 , and mGlu 8 (Emery et al, 2012;Gregory et al, 2012;Jalan-Sakrikar et al, 2014). For example, stimulus-bias is evident when comparing orthosteric agonists L-AP4 [L-2-amino-4-phosphonobutyrate] and LSP4-2022 [(2S)-2-amino-4-([[4-(carboxymethoxy) .…”

“…Biased modulation is not limited to mGlu 5 PAMs, both positive and negative modulators of group III receptors have been suggested to induce biased receptor signaling Jalan-Sakrikar et al, 2014). The extent and prevalence of biased modulators is likely to be highly underappreciated.…”

Association study of GRM7 polymorphisms and schizophrenia in the Chinese Han population

“…Some polymorphisms of metabotropic glutamate receptor 7 (GRM7) have also been found to be associated with schizophrenia [1,3,10,18,19]. Jajodia designed the study to explore the association between GRM7 and schizophrenia through in 840 schizophrenic cases and 876 healthy subjects in the Indian population.…”

“…GRM7 belongs to the group III of metabotropic glutamate receptors and plays a role in glutamatergic neurotransmission [3,19]. Meanwhile, the metabotropic glutamate receptors belongs to the family of G protein-coupled receptors (GPCRs) which are related to numerous vital signal pathways and human diseases.…”

“…These receptors are associated with the inhibition of the cyclic AMP cascade. GRM7 is predominately expressed in the presynapse, where it modulates the release of both glutamate and gamma-aminobutyric acid (GABA) [19]. Glutamate is one of the most important excitatory neurotransmitters for the central nervous system (CNS).…”