Illuminating Phenylazopyridines To Photoswitch Metabotropic Glutamate Receptors: From the Flask to the Animals.
Phenylazopyridines are photoisomerizable compounds with high potential to control biological functions with light. We have obtained a series of phenylazopyridines with light dependent activity as negative allosteric modulators (NAM) of metabotropic glutamate receptor subtype 5 (mGlu5). Here we describe the factors needed to achieve an operational molecular photoisomerization and its effective translation intoin vitroandin vivoreceptor photoswitching, which includes zebrafish larva motility and the regulation of the antinociceptive effects in mice. The combination of light and some specific phenylazopyridine ligands displays atypical pharmacological profiles, including light-dependent receptor overactivation, which can be observed bothin vitroandin vivo. Remarkably, the localized administration of light and a photoswitchable compound in the peripheral tissues of rodents or in the brain amygdalae results in an illumination-dependent analgesic effect. The results reveal a robust translation of the phenylazopyridine photoisomerization to a precise photoregulation of biological activity.
MCS, Laboratory of Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain; Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Xavier
X
Gómez-Santacana
Institute for Bioengineering of Catalonia (IBEC) , Barcelona, Spain.
Silvia
S
Pittolo
Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
Xavier
X
Rovira
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, Barcelona, Spain; Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
Marc
M
Lopez
Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
Charleine
C
Zussy
Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB) , Barcelona, Spain.
James A R
JA
Dalton
Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
Adèle
A
Faucherre
Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
Chris
C
Jopling
Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
Jean-Philippe
JP
Pin
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, Barcelona, Spain; Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
Francisco
F
Ciruela
Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
Cyril
C
Goudet
Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Network Biomedical Research Center on Mental Health (CIBERSAM), Madrid, Spain.
Jesús
J
Giraldo
Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Network Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
Pau
P
Gorostiza
MCS, Laboratory of Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) , Barcelona, Spain.
Amadeu
A
Llebaria