新型高效GABA摄取抑制剂，对源自（R）-和（S）-脯氨酸及同源吡咯烷-2-链烷酸的GAT-1和GAT-3具有选择性。
New highly potent GABA uptake inhibitors selective for GAT-1 and GAT-3 derived from (R)- and (S)-proline and homologous pyrrolidine-2-alkanoic acids.
作者信息
Fülep Günther H, Hoesl Cornelia E, Höfner Georg, Wanner Klaus T
机构信息
Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Germany.
出版信息
Eur J Med Chem. 2006 Jul;41(7):809-24. doi: 10.1016/j.ejmech.2006.01.019.
We synthesized proline and pyrrolidine-2-alkanoic acid derivatives in their enantiomerically pure form and evaluated them for their affinity to the GABA transport proteins GAT-1 and GAT-3. Among the compounds presented herein, (R)-pyrrolidine-2-acetic acid (R)-4d substituted with a 2-[tris(4-methoxyphenyl)methoxy]ethyl residue at the nitrogen atom showed the highest affinity at GAT-3 (IC(50) = 3.1 microM) comparable with the well-known GAT-3 blocker (S)-SNAP-5114. Compound (R)-4d displayed excellent subtype selectivity for GAT-3 (GAT-3:GAT-1 = 20:1). (S)-2-pyrrolidineacetic acid derivatives (S)-4b provided with a 4,4-diphenylbut-3-en-1-yl moiety and (S)-4c substituted with a 4,4-[di(3-methylthiophen-2-yl)]phenylbut-3-en-1-yl residue at the nitrogen atom exhibited IC(50) values of 0.396 microM and 0.343 microM at the GAT-1 protein, respectively.
我们合成了对映体纯形式的脯氨酸和吡咯烷 -2-链烷酸衍生物，并评估了它们对γ-氨基丁酸转运蛋白GAT-1和GAT-3的亲和力。在本文介绍的化合物中，在氮原子上被2-[三(4-甲氧基苯基)甲氧基]乙基残基取代的(R)-吡咯烷-2-乙酸(R)-4d对GAT-3表现出最高亲和力（IC(50)=3.1微摩尔），与著名的GAT-3阻滞剂(S)-SNAP-5114相当。化合物(R)-4d对GAT-3表现出优异的亚型选择性（GAT-3:GAT-1 = 20:1）。在氮原子上带有4,4-二苯基丁-3-烯-1-基部分的(S)-2-吡咯烷乙酸衍生物(S)-4b和被4,4-[二(3-甲基噻吩-2-基)]苯基丁-3-烯-1-基残基取代的(S)-4c在GAT-1蛋白上的IC(50)值分别为0.396微摩尔和0.343微摩尔。
Zotero 插件