title: Structure-activity relationships for negative allosteric mGluR5 modulators.
abstract: A series of compounds based on the mGluR5-selective ligand 2-methyl-6-(phenylethynyl)pyridine (MPEP) were designed and synthesized. The compounds were found to be either structural analogues of MPEP, substituted monomers, or dimeric analogues. All compounds retained mGluR5 selectivity with only weak or no activity at other mGluRs or iGluRs. The substituted analogue, 1,3-bis(pyridin-2-ylethynyl)benzene (19), is a potent negative modulator at mGluR5, whereas all other compounds lost potency relative to MPEP and showed that activity is highly dependent on the position of the nitrogen atom in the pyridine moieties. A homology modeling and ligand docking study was used to understand the binding mode and the observed selectivity of compound 19.
authors.affiliation: Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Birgitte H
authors.initials: BH
authors.lastname: Kaae
authors.forename: Kasper
authors.initials: K
authors.lastname: Harpsøe
authors.forename: Trine
authors.initials: T
authors.lastname: Kvist
authors.forename: Jesper M
authors.initials: JM
authors.lastname: Mathiesen
authors.forename: Christina
authors.initials: C
authors.lastname: Mølck
authors.forename: David
authors.initials: D
authors.lastname: Gloriam
authors.forename: Hermogenes N
authors.initials: HN
authors.lastname: Jimenez
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Uberti
authors.forename: Søren M
authors.initials: SM
authors.lastname: Nielsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Per
authors.initials: P
authors.lastname: Sauerberg
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D019281:Dimerization; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C573496:1,3-bis(pyridin-2-ylethynyl)benzene; D000480:Alkynes; D014151:Anti-Anxiety Agents; C578935:GRM5 protein, human; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid