Kaae Birgitte H, Harpsøe Kasper, Kastrup Jette S, Sanz Alberto Contreras, Pickering Darryl S, Metzler Bjørn, Clausen Rasmus P, Gajhede Michael, Sauerberg Per, Liljefors Tommy, Madsen Ulf
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Chem Biol. 2007 Nov;14(11):1294-303. doi: 10.1016/j.chembiol.2007.10.012.
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.
离子型谷氨酸受体的二聚体正变构调节剂在电生理实验中进行了设计、合成及药理学表征。所设计的化合物为芳基丙基磺酰胺二聚体，且构建时未使用连接子。单体芳基丙基磺酰胺衍生自已知调节剂，靶向AMPA受体的环噻嗪结合位点。制备了两种构建的二聚体的三种立体异构体——R,R、内消旋体和S,S，体外测试表明R,R形式是最有效的立体异构体。联芳基丙基磺酰胺的效力显著提高，比相应单体高出三个多数量级。二聚体(R,R)-2a与GluR2-S1S2J构建体共结晶，X射线晶体学分析表明(R,R)-2a桥接两个相邻GluR2亚基上的两个相同结合口袋。因此，这是同聚二聚体桥接两个相同受体结合位点的生物结构证据。
