Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series

Bioorg Med Chem Lett. 2011 Jun 1;21(11):3243-7. doi: 10.1016/j.bmcl.2011.04.047. Epub 2011 Apr 20.

Abstract

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.

Publication types

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

MeSH terms

  • Acetylene / analogs & derivatives*
  • Acetylene / chemistry
  • Acetylene / pharmacology
  • Animals
  • Binding, Competitive / drug effects
  • Cells, Cultured
  • Ligands
  • Mice
  • Molecular Structure
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology

Substances

  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Ligands
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • phenylacetylene
  • Acetylene