In vitro and in vivo characterization of MPEP, an allosteric modulator of the metabotropic glutamate receptor subtype 5: review article.
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 mGlu(5) 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 mGlu(5) receptors as a potentially important therapeutic target particularly for the treatment of pain and anxiety.
Kuhn
R
R
Nervous System Research, Novartis, Pharma AG, Basel, Switzerland. Rainer.kuhn@pharma.novartis.com
Pagano
A
A
Stoehr
N
N
Vranesic
I
I
Flor
P J
PJ
Lingenhöhl
K
K
Spooren
W
W
Gentsch
C
C
Vassout
A
A
Pilc
A
A
Gasparini
F
F
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism* / Q000627:therapeutic use; D008024:Ligands; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine