TY - JOUR
T1 - Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites
AU - Kaae, Birgitte Høiriis
AU - Harpsøe, Kasper
AU - Kastrup, Jette Sandholm Jensen
AU - Sanz, Alberto Contreras
AU - Pickering, Darryl Scott
AU - Metzler, Bjørn
AU - Clausen, Rasmus Prætorius
AU - Gajhede, Michael
AU - Sauerberg, Per
AU - Liljefors, Tommy
AU - Madsen, Ulf
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
KW - Former Faculty of Pharmaceutical Sciences
KW - Binding Sites
KW - Crystallography, X-Ray
KW - Dimerization
KW - Ligands
KW - Models, Molecular
KW - Nuclear Magnetic Resonance, Biomolecular
KW - Protein Conformation
KW - Receptors, AMPA
KW - Stereoisomerism
U2 - 10.1016/j.chembiol.2007.10.012
DO - 10.1016/j.chembiol.2007.10.012
M3 - Journal article
C2 - 18022568
SN - 1074-5521
VL - 14
SP - 1294
EP - 1303
JO - Chemistry & Biology
JF - Chemistry & Biology
IS - 11
ER -