Small Molecule mGlu3 NAMs as Therapeutics for CNS Disorders


The Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) has a mission to promote the translation of advances in basic science towards novel therapeutics. They have recruited faculty and staff with experience at over 10 different pharmaceutical companies to ensure a diverse set of approaches, techniques and philosophies to advancing compounds. Together they aim to de-risk drug discovery programs.


About the Target

Targeting metabotropic glutamate receptor 3 (mGlu3) has been linked as a potential therapeutic to many neurological disorders and well as oncology through the use of dual specific mGlu2/3 Antagonists (LY341495, RO4491533, MGS0039, RO4988546). These dual specific compounds have shown efficacy in models for:


  • Anxiety or OCD (Eur J. Pharmacol, 2008, 592, 96; Psychopharmacology 2006, 186, 587) Depressive
  • Disorders (Neuropharmacology 2013, 65, 29; Neuropharmacology 2013 64, 337)
  • Alzheimer’s disease (Mol. Psych. 2014, 79, 887; J. Neuroscience 2010, 30, 3870)
  • Addiction Withdrawal (Behav. Brain Res. 2013, 246, 24)


In efforts to determine which of these disease states are being treated by the mGlu3 action compared to the mGlu2 action, the group has developed a Tool compound. This mGlu3 NAM Tool Compound, used for proof of concept studies, has shown to be efficacious in two separate animal models thus far (Marble burying for anxiety, and forced swim for Depression). See the figures below for the data as well as the table for the tool compound characteristics.


Lead status

  • The VCNDD has developed proprietary highly selective CNS penetrant in vivo mGlu3 NAMs that are selective over mGlu2, unlike current competing compounds, which are non-selective.
  • Low to moderate clearance has been observed with certain analogs in rat IV PK studies.
  • Multiple compounds with clean P450 inhibition profiles have been identified.
  • This is an earlier stage program, Hit to Lead Optimization.



Then only known competition is one dual mGlu2/3 NAM compound from Roche (decoglurant) is in the clinic, Phase II studies for Depression and Major Depressive Disorder.



Licensing Contact

Mike Villalobos

Tech ID:
Small Molecule