Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites

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Birgitte Høiriis Kaae, Kasper Harpsøe, Jette Sandholm Jensen Kastrup, Alberto Contreras Sanz, Darryl Scott Pickering, Bjørn Metzler, Rasmus Prætorius Clausen, Michael Gajhede, Per Sauerberg, Tommy Liljefors, Ulf Madsen

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.
Original languageEnglish
JournalChemistry & Biology
Volume14
Issue number11
Pages (from-to)1294-303
Number of pages10
ISSN1074-5521
DOIs
Publication statusPublished - 2007

    Research areas

  • The Faculty of Pharmaceutical Sciences - Binding Sites, Crystallography, X-Ray, Dimerization, Ligands, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Receptors, AMPA, Stereoisomerism

ID: 3469632