New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III
| Autor: | Robb Brodbeck, Emmanuelle Sagot, Zeinab Assaf, Mette N. Erichsen, Thierry Gefflaut, Christian Thomsen, Walden E. Bjørn-Yoshimoto, Amélie S. Tora, Birgitte Nielsen, Tine B. Stensbøl, Lennart Bunch, Tri H. V. Huynh, Cyril Goudet, Jean-Philippe Pin |
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| Přispěvatelé: | Department of Drug Design and Pharmacology [Copenhagen] (ILF), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Clermont-Ferrand (ICCF), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), H. Lundbeck A/S, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Glutamic Acid Pharmacology Crystallography X-Ray Receptors Metabotropic Glutamate 01 natural sciences Structure-Activity Relationship 03 medical and health sciences Drug Discovery Animals Humans [CHIM]Chemical Sciences Cells Cultured Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Metabotropic glutamate receptor 5 Metabotropic glutamate receptor 4 Metabotropic glutamate receptor 7 Rats 0104 chemical sciences HYDIA HEK293 Cells 030104 developmental biology Biochemistry Metabotropic glutamate receptor Molecular Medicine Metabotropic glutamate receptor 1 Metabotropic glutamate receptor 3 Metabotropic glutamate receptor 2 |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2016, 59, pp.914-924. ⟨10.1021/acs.jmedchem.5b01333⟩ Journal of Medicinal Chemistry, 2016, 59, pp.914-924. ⟨10.1021/acs.jmedchem.5b01333⟩ |
| ISSN: | 0022-2623 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.5b01333⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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