title: Reprint of Pharmacological and molecular characterization of the positive allosteric modulators of metabotropic glutamate receptor 2.
abstract: The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2PAMs are therefore carried out here using the radiolabeled mGlu2agonist3[H]-LY354740 and mGlu2PAM3[H]-2,2,2-TEMPS. A multidimensional approach to the PAM mechanism of action shows that mGlu2PAMs increase the affinity of3[H]-LY354740 for the orthosteric site of mGlu2 as well as the number of3[H]-LY354740 binding sites.3[H]-2,2,2-TEMPS binding is also enhanced by the presence of LY354740. New residues in the allosteric rat mGlu2 binding pocket are identified to be crucial for the PAMs ligand binding, among these Tyr3.40and Asn5.46. Also of remark, in the described experimental conditions S731A (Ser5.42) residue is important only for the mGlu2PAM LY487379 and not for the compound PAM-1: an example of the structural differences among these mGlu2PAMs. This study provides a summary of the information generated in the past decade on mGlu2PAMs adding a detailed molecular investigation of PAM binding mode. Differences among mGlu2PAM compounds are discussed as well as the mGlu2 regions interacting with mGlu2PAM and NAM agents and residues driving mGlu2 PAM selectivity. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, NORD Neuroscience, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Lundström
authors.affiliation: Discovery Chemistry, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel, CH4070, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Bissantz
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, NORD Neuroscience, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Beck
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, NORD Neuroscience, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Dellenbach
authors.affiliation: Discovery Chemistry, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel, CH4070, Switzerland.
authors.forename: T J
authors.initials: TJ
authors.lastname: Woltering
authors.affiliation: Discovery Chemistry, Roche Innovation Center Basel, Grenzacherstrasse 124, Basel, CH4070, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Wichmann
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, NORD Neuroscience, Switzerland. Electronic address: silviagatti.mcarthur@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Gatti
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D017433:Protein Structure, Secondary; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology*
chemical_list: D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid; C104753:eglumetad
keywords: 1-Butyl-4-[4-(2,6-dimethyl-pyridin-3-yloxy)-3-fluoro-phenyl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile; 2,2,2-TEMPS; HYDIA; LY354740; LY487379; Metabotropic glutamate receptor; Negative allosteric modulators; PAM-1; Positive allosteric modulators; RO5488608; mGlu(2); mGlu(3); mGluR