title: New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III.
abstract: The metabotropic glutamate (Glu) receptors (mGluRs) play key roles in modulating excitatory neurotransmission in the brain. In all, eight subtypes have been identified and divided into three groups, group I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6-8). In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over the remaining mGluR subtypes. A modeling study and redesign of the core scaffold led to the stereoselective synthesis of four new conformationally restricted Glu analogues, 2a-d. Most interestingly, 2a retained a selective agonist activity profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III, subtypes mGlu4,6,8. In general, 2d was 20-fold more potent than 2c and potently activated mGlu4,6,8 in the low-mid nanomolar range.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Tri H V
authors.initials: TH
authors.lastname: Huynh
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Mette N
authors.initials: MN
authors.lastname: Erichsen
authors.affiliation: Institute of Functional Genomics, CNRS, UMR5203, University of Montpellier , 34094 Montpellier, France.|INSERM, U1191 , 34094 Montpellier, France.
authors.forename: Amélie S
authors.initials: AS
authors.lastname: Tora
authors.affiliation: Institute of Functional Genomics, CNRS, UMR5203, University of Montpellier , 34094 Montpellier, France.|INSERM, U1191 , 34094 Montpellier, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
authors.affiliation: Institut de Chimie de Clermont-Ferrand, Clermont Université, Université Blaise Pascal, BP 10448 , 63000 Clermont-Ferrand, France.|CNRS, UMR6296, ICCF, BP 80026 , 63177 Aubière, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sagot
authors.affiliation: Institut de Chimie de Clermont-Ferrand, Clermont Université, Université Blaise Pascal, BP 10448 , 63000 Clermont-Ferrand, France.|CNRS, UMR6296, ICCF, BP 80026 , 63177 Aubière, France.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Assaf
authors.affiliation: H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Thomsen
authors.affiliation: H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Robb
authors.initials: R
authors.lastname: Brodbeck
authors.affiliation: H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Walden E
authors.initials: WE
authors.lastname: Bjørn-Yoshimoto
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.affiliation: Institute of Functional Genomics, CNRS, UMR5203, University of Montpellier , 34094 Montpellier, France.|INSERM, U1191 , 34094 Montpellier, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.affiliation: Institut de Chimie de Clermont-Ferrand, Clermont Université, Université Blaise Pascal, BP 10448 , 63000 Clermont-Ferrand, France.|CNRS, UMR6296, ICCF, BP 80026 , 63177 Aubière, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gefflaut
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid