Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites.
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.
Kaae
Birgitte H
BH
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Harpsøe
Kasper
K
Kastrup
Jette S
JS
Sanz
Alberto Contreras
AC
Pickering
Darryl S
DS
Metzler
Bjørn
B
Clausen
Rasmus P
RP
Gajhede
Michael
M
Sauerberg
Per
P
Liljefors
Tommy
T
Madsen
Ulf
U
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
D008024:Ligands; D018091:Receptors, AMPA