title: Discovery and characterization of non-competitive antagonists of group I metabotropic glutamate receptors.
abstract: We have investigated the mechanism of inhibition of the new group I mGluR antagonists CPCCOEt and MPEP and determined that both compounds have a non-competitive mode of inhibition. Furthermore using chimeric/mutated receptors constructs we have found that these antagonists act at a novel pharmacological site located in the trans-membrane (TM). Specific non-conserved amino acid residues in the TM domain have been identified which are necessary for the inhibition by CPCCOEt and MPEP of the mGlul and mGlu5 receptors, respectively. Using molecular modeling a model of the TM domain was built for both mGlu1 and mGlu5 receptor subtypes. Docking of CPCCOEt and MPEP into their respective model allowed the modelisation of the novel binding site.
authors.affiliation: Novartis Pharma AG, Nervous System Research, Basel, Switzerland. fabrizio.gasparini@pharma.novartis.com
authors.forename: F
authors.initials: F
authors.lastname: Gasparini
authors.forename: P
authors.initials: P
authors.lastname: Floersheim
authors.forename: P J
authors.initials: PJ
authors.lastname: Flor
authors.forename: M
authors.initials: M
authors.lastname: Heinrich
authors.forename: W
authors.initials: W
authors.lastname: Inderbitzin
authors.forename: D
authors.initials: D
authors.lastname: Ott
authors.forename: A
authors.initials: A
authors.lastname: Pagano
authors.forename: C
authors.initials: C
authors.lastname: Stierlin
authors.forename: N
authors.initials: N
authors.lastname: Stoehr
authors.forename: I
authors.initials: I
authors.lastname: Vranesic
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
mesh_terms: D001665:Binding Sites; D008958:Models, Molecular; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1