title: Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu5negative allosteric modulation.
abstract: Modulation of metabotropic glutamate receptor 5 (mGlu5) with partial allosteric antagonists has received increased interest due to their favourable in vivo activity profiles compared to the unfavourable side-effects of full inverse agonists. Here we report on a series of bispyridine benzene derivatives with a functional molecular switch affecting antagonistic efficacy, shifting from inverse agonism to partial antagonism with only a single change in the substitution pattern of the benzene ring. These efficacy changes are explained through computational docking, revealing two different receptor conformations of different energetic stability and different positional isomer binding preferences.
authors.affiliation: MCS, Laboratory of Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain; Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; Nanoprobes and Nanoswitches, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac, 08028, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gómez-Santacana
authors.affiliation: Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; Network Biomedical Research Center on Mental Health (CIBERSAM), Spain.
authors.forename: James A R
authors.initials: JAR
authors.lastname: Dalton
authors.affiliation: Department of Neurosciences, Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Rovira
authors.affiliation: Department of Neurosciences, Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Pin
authors.affiliation: Department of Neurosciences, Institute of Functional Genomics, Université de Montpellier, Unité Mixte de Recherche 5302 CNRS, Montpellier, France; Unité de recherche U1191, INSERM, Montpellier, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goudet
authors.affiliation: Nanoprobes and Nanoswitches, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac, 08028, Barcelona, Spain; Network Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Gorostiza
authors.affiliation: Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain; Network Biomedical Research Center on Mental Health (CIBERSAM), Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Giraldo
authors.affiliation: MCS, Laboratory of Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain. Electronic address: amadeu.llebaria@iqac.csic.es.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001554:Benzene / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D064529:Receptor, Metabotropic Glutamate 5; D001554:Benzene
keywords: Antagonist; Inverse agonist; Isomers; NAM; Partial efficacy; mGlu(5)