33 research outputs found
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
An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia
Descripción de ciperáceas y gramÃneas de Tierra del Fuego.Facultad de Ciencias Naturales y Muse
PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems
Positive
allosteric modulators (PAMs) of the M<sub>1</sub> subtype
of muscarinic acetylcholine receptor have attracted intense interest
as an exciting new approach for improving the cognitive deficits in
schizophrenia and Alzheimer’s disease. Recent evidence suggests
that the presence of intrinsic agonist activity of some M<sub>1</sub> PAMs may reduce efficacy and contribute to adverse effect liability.
However, the M<sub>1</sub> PAM PF-06827443 was reported to have only
weak agonist activity at human M<sub>1</sub> receptors but produced
M<sub>1</sub>-dependent adverse effects. We now report that PF-06827443
is an allosteric agonist in cell lines expressing rat, dog, and human
M<sub>1</sub> and use of inducible cell lines shows that agonist activity
of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443
is an agonist in native tissue preparations and induces behavioral
convulsions in mice similar to other ago-PAMs. These findings suggest
that PF-06827443 is a robust ago-PAM, independent of species, in cell
lines and native systems
Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu<sub>1</sub>), Based on an <i>N</i>‑(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu<sub>1</sub> Receptors Found in Schizophrenics
The
therapeutic potential of selective mGlu<sub>1</sub> activation
is vastly unexplored relative to the other group I mGlu receptor,
mGlu<sub>5</sub>; therefore, our lab has focused considerable effort
toward developing mGlu<sub>1</sub> positive allosteric modulators
(PAMs) suitable as in vivo proof of
concept tool compounds. Optimization of a series of mGlu<sub>1</sub> PAMs based on an <i>N</i>-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)Âphenyl)-3-methylfuran-2-carboxamide
scaffold provided <b>17e</b>, a potent (mGlu<sub>1</sub> EC<sub>50</sub> = 31.8 nM) and highly CNS penetrant (brain to plasma ratio
(<i>K</i><sub>p</sub>) of 1.02) mGlu<sub>1</sub> PAM tool
compound, that potentiated not only wild-type human mGlu<sub>1</sub> but also mutant mGlu<sub>1</sub> receptors derived from deleterious <i>GRM1</i> mutations found in schizophrenic patients. Moreover,
both electrophysiological and in vivo studies indicate the mGlu<sub>1</sub> ago-PAMs/PAMs do not possess the same epileptiform adverse
effect liability as mGlu<sub>5</sub> ago-PAMs/PAMs and maintain temporal
activity suggesting a broader therapeutic window