title: In vitro and in vivo characterization of MPEP, an allosteric modulator of the metabotropic glutamate receptor subtype 5: review article.
abstract: 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.
authors.affiliation: Nervous System Research, Novartis, Pharma AG, Basel, Switzerland. Rainer.kuhn@pharma.novartis.com
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.forename: A
authors.initials: A
authors.lastname: Pagano
authors.forename: N
authors.initials: N
authors.lastname: Stoehr
authors.forename: I
authors.initials: I
authors.lastname: Vranesic
authors.forename: P J
authors.initials: PJ
authors.lastname: Flor
authors.forename: K
authors.initials: K
authors.lastname: Lingenhöhl
authors.forename: W
authors.initials: W
authors.lastname: Spooren
authors.forename: C
authors.initials: C
authors.lastname: Gentsch
authors.forename: A
authors.initials: A
authors.lastname: Vassout
authors.forename: A
authors.initials: A
authors.lastname: Pilc
authors.forename: F
authors.initials: F
authors.lastname: Gasparini
mesh_terms: 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
chemical_list: 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