Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM

Bioorg Med Chem Lett. 2012 Jun 15;22(12):3921-5. doi: 10.1016/j.bmcl.2012.04.112. Epub 2012 Apr 30.

Abstract

Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 μM and is inactive against mGlu(5).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Cell Line
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Drug Discovery
  • Glutamic Acid / metabolism
  • Humans
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / metabolism
  • Molecular Probes / chemical synthesis*
  • Molecular Probes / pharmacology
  • Permeability
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Sensitivity and Specificity
  • Structure-Activity Relationship

Substances

  • ML289
  • Molecular Probes
  • Piperidines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • VU0092273
  • metabotropic glutamate receptor 3
  • Glutamic Acid