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Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site

Authors
  • Frédéric Knoflach
  • Vincent Mutel
  • Synèse Jolidon
  • James N. C. Kew
  • Pari Malherbe
  • Eric Vieira
  • Jürgen Wichmann
  • John A. Kemp
Publisher
The National Academy of Sciences
Publication Date
Oct 23, 2001
Source
PMC
Keywords
Disciplines
  • Biology
  • Chemistry
License
Unknown

Abstract

We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to localize amino acids in the receptor transmembrane region critical for these enhancing properties. Finally, the compounds potentiated synaptically evoked mGlu1 receptor responses in rat brain slices. The discovery of selective positive allosteric modulators of mGlu1 receptors opens up the possibility to develop a similar class of compounds for other family 3 G protein-coupled receptors.

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