There is a need to identify subtype-specific ligands for mGlu receptors to elucidate the potential of these receptors for
the treatment of nervous system disorders. To date, most mGlu receptor antagonists are amino acid-like compounds acting as
competitive antagonists at the glutamate binding site located in the large extracellular N-terminal domain.
We have characterized novel subtype-selective mGlu5 receptor antagonists which are structurally unrelated to competitive mGlu receptor ligands. Using a series of chimeric receptors
and point mutations we demonstrate that these antagonists act as inverse agonists with a novel allosteric binding site in
the seven-transmembrane domain. Recent studies in animal models implicate mGlu5 receptors as a potentially important therapeutic target particularly for the treatment of pain and anxiety.
Keywords: Group I metabotropic glutamate receptors - MPEP - SIB-1757 - Anxiety - Pain
Received July 2, 2001 Accepted August 6, 2001 Published online September 10, 2002