title: Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites.
abstract: Dimeric positive allosteric modulators of ionotropic glutamate receptors were designed, synthesized, and characterized pharmacologically in electrophysiological experiments. The designed compounds are dimers of arylpropylsulfonamides and have been constructed without a linker. The monomeric arylpropylsulfonamides were derived from known modulators and target the cyclothiazide-binding site at the AMPA receptors. The three stereoisomers--R,R, meso, and S,S--of the two constructed dimers were prepared, and in vitro testing showed the R,R forms to be the most potent stereoisomers. The biarylpropylsulfonamides have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2 subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Birgitte H
authors.initials: BH
authors.lastname: Kaae
authors.forename: Kasper
authors.initials: K
authors.lastname: Harpsøe
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
authors.forename: Alberto Contreras
authors.initials: AC
authors.lastname: Sanz
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Bjørn
authors.initials: B
authors.lastname: Metzler
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Per
authors.initials: P
authors.lastname: Sauerberg
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D018091:Receptors, AMPA