Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5779-85. doi: 10.1016/j.bmcl.2013.09.001. Epub 2013 Sep 10.


Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.

Keywords: Allosteric modulator; Anxiety; CNS; Glutamate; mGlu(5).

Publication types

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

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Site / drug effects
  • Animals
  • Anxiety / drug therapy*
  • Benzamides / chemistry
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use*
  • Mice
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacokinetics
  • Thiazoles / therapeutic use*


  • Benzamides
  • Receptor, Metabotropic Glutamate 5
  • Thiazoles
  • VU0409106