Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator

Bioorg Med Chem Lett. 2011 Dec 1;21(23):6955-9. doi: 10.1016/j.bmcl.2011.09.131. Epub 2011 Oct 8.

Abstract

Herein we report the discovery and SAR of a novel antagonist of metabotropic glutamate receptor 4 (mGlu(4)). The antagonist was discovered via a molecular switch from a closely related mGlu(4) positive allosteric modulator (PAM). This antagonist (VU0448383) displays an IC(50) value of 8.2±0.4 μM and inhibits an EC(80) glutamate response by 63.1±6.6%.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Cells, Cultured
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Pyridines
  • Receptors, Metabotropic Glutamate
  • VU0448383
  • metabotropic glutamate receptor 4