Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7

ACS Chem Neurosci. 2014 Dec 17;5(12):1221-37. doi: 10.1021/cn500153z. Epub 2014 Oct 9.


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.

Keywords: Allosteric modulator; electrophysiology; hippocampus; metabotropic glutamate receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemistry
  • Acetanilides / pharmacology
  • Animals
  • Benzoates / pharmacology
  • CHO Cells
  • Calcium / metabolism
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agents / chemistry*
  • Excitatory Amino Acid Agents / pharmacology*
  • Excitatory Postsynaptic Potentials / drug effects
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Glutamic Acid / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • HEK293 Cells
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • In Vitro Techniques
  • Male
  • Mice, Inbred C57BL
  • Picolinic Acids / chemistry
  • Picolinic Acids / pharmacology
  • Propionates / pharmacology
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship
  • Thallium / metabolism
  • Transfection


  • 2-amino-4-phosphono-propinate
  • 3,4-dicarboxyphenylglycine
  • Acetanilides
  • Benzoates
  • Excitatory Amino Acid Agents
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Picolinic Acids
  • Propionates
  • Pyrroles
  • Receptors, Metabotropic Glutamate
  • VU0155094
  • VU0422288
  • metabotropic glutamate receptor 7
  • Glutamic Acid
  • Thallium
  • Calcium
  • Glycine