OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity

Xavier Rovira; Ana Trapero; Silvia Pittolo; Charleine Zussy; Adèle Faucherre; Chris Jopling; Jesús Giraldo; Jean-Philippe Pin; Pau Gorostiza; Cyril Goudet; Amadeu Llebaria

doi:10.1016/j.chembiol.2016.06.013

OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity

Cell Chem Biol. 2016 Aug 18;23(8):929-34. doi: 10.1016/j.chembiol.2016.06.013. Epub 2016 Jul 28.

Authors

Affiliations

¹ Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, 34000 Montpellier, France; INSERM, U1191, 34000 Montpellier, France.
² Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain; Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain.
³ Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain.
⁴ Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
⁵ Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain; Network Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Poeta Mariano Esquillor s/n, Zaragoza 50018, Spain; ICREA, Pg. Lluís Companys, 23, Barcelona 08010, Spain. Electronic address: [email protected].
⁶ Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, 34000 Montpellier, France; INSERM, U1191, 34000 Montpellier, France. Electronic address: [email protected].
⁷ Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain. Electronic address: [email protected].

PMID: 27478159
DOI: 10.1016/j.chembiol.2016.06.013

Abstract

OptoGluNAM4.1, a negative allosteric modulator (NAM) of metabotropic glutamate receptor 4 (mGlu4) contains a reactive group that covalently binds to the receptor and a blue-light-activated, fast-relaxing azobenzene group that allows reversible receptor activity photocontrol in vitro and in vivo. OptoGluNAM4.1 induces light-dependent behavior in zebrafish and reverses the activity of the mGlu4 agonist LSP4-2022 in a mice model of chronic pain, defining a photopharmacological tool to better elucidate the physiological roles of the mGlu4 receptor in the nervous system.

MeSH terms

Allosteric Regulation / drug effects
Allosteric Regulation / radiation effects
Animals
Azo Compounds / chemistry
Azo Compounds / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Light*
Mice
Mice, Inbred C57BL
Pain Threshold / drug effects
Pyrrolidonecarboxylic Acid / analogs & derivatives*
Pyrrolidonecarboxylic Acid / chemistry
Pyrrolidonecarboxylic Acid / pharmacology
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship
Time Factors
Zebrafish / metabolism

Substances

Azo Compounds
OptoGluNAM4.1
Receptors, Metabotropic Glutamate
Pyrrolidonecarboxylic Acid
metabotropic glutamate receptor 4