Genetic Reduction or Negative Modulation of mGlu₇ Does Not Impact Anxiety and Fear Learning Phenotypes in a Mouse Model of <i>MECP2</i> Duplication Syndrome

Rett syndrome and <i>MECP2</i> Duplication syndrome are neurodevelopmental disorders attributed to loss-of-function mutations in, or duplication of, the gene encoding methyl-CpG-binding protein 2 (MeCP2), respectively. We recently reported decreased expression and function of the metabotropic glutamate receptor 7 (mGlu₇) in a mouse model of Rett syndrome. Positive allosteric modulation of mGlu₇ activity was sufficient to improve several disease phenotypes including cognition. Here, we tested the hypothesis that mGlu₇ expression would be reciprocally regulated in a mouse model of <i>MECP2</i> Duplication syndrome, such that negative modulation of mGlu₇ activity would exert therapeutic benefit. To the contrary, we report that mGlu₇ is not functionally increased in mice overexpressing MeCP2 and that neither genetic nor pharmacological reduction of mGlu₇ activity impacts phenotypes that are antiparallel to those observed in Rett syndrome model mice. These data expand our understanding of how mGlu₇ expression and function is affected by changes in MeCP2 dosage and have important implications for the therapeutic development of mGlu₇ modulators

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

The metabotropic glutamate receptor 7 (mGlu7) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution resulted in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu7–global KO mice, mGlu7-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population

Discovery of VU6005649, a CNS Penetrant mGlu_7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5‑<i>a</i>]pyrimidines

Herein, we report the structure–activity relationships within a series of mGlu₇ PAMs based on a pyrazolo­[1,5-<i>a</i>]­pyrimidine core with excellent CNS penetration (<i>K</i>_ps > 1 and <i>K</i>_p,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu_7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating <i>in vivo</i> efficacy in a mouse contextual fear conditioning model

Discovery, Synthesis, and Preclinical Characterization of <i>N</i>‑(3-Chloro-4-fluorophenyl)‑1<i>H</i>‑pyrazolo[4,3‑<i>b</i>]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄)

The efficacy of positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 4 (mGlu₄) in preclinical rodent models of Parkinson’s disease has been established by a number of groups. Here, we report an advanced preclinically characterized mGlu₄ PAM, <i>N</i>-(3-chloro-4-fluorophenyl)-1<i>H</i>-pyrazolo­[4,3-<i>b</i>]­pyridin-3-amine (VU0418506). We detail the discovery of VU0418506 starting from a common picolinamide core scaffold and evaluation of a number of amide bioisosteres leading to the novel pyrazolo­[4,3-<i>b</i>]­pyridine head group. VU0418506 has been characterized as a potent and selective mGlu₄ PAM with suitable in vivo pharmacokinetic properties in three preclinical safety species