A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: L-anti-endo-3,4-methanopyrrolidine dicarboxylate.
A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: L-anti-endo-3,4-methanopyrrolidine dicarboxylate.
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前脑突触体中钠依赖性谷氨酸转运蛋白的构象限制竞争性抑制剂：L-抗内-3,4-甲基吡咯烷二羧酸酯。
DOI：
10.1016/0304-3940(94)90019-1
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发表时间：
1994
影响因子：
2.5
通讯作者：
Chamberlin,AR
中科院分区：
文献类型：
--
作者：
Bridges,RJ;Lovering,FE;Koch,H;Cotman,CW;Chamberlin,AR
研究了一系列 1-3,4-甲基吡咯烷二羧酸酯异构体作为大鼠前脑突触体中高亲和力、钠依赖性谷氨酸转运蛋白的潜在抑制剂。在测试的异构体中，只有l-抗-内-3,4-甲基吡咯烷二羧酸酯（l-抗-内-MPDC）阻断[3H]d-天冬氨酸（一种非代谢底物）的摄取。动力学分析表明，l-抗-endo-MPDC 是一种有效的竞争性抑制剂（Ki= 5μM），与l-谷氨酸和l-反式-2,4-吡咯烷二羧酸酯（l-trans-2,4-PDC）相当。利用l-谷氨酸、l-trans-2,4-PDC 和l-anti-endo-MPDC 的构象分析来完善转运蛋白结合位点的药效团模型。
A series ofl-3,4-methanopyrrolidine dicarboxylate isomers were investigated as potential inhibitors of the high affinity, sodium-dependent glutamate transporter in rat forebrain synaptosomes. Of the isomers tested, onlyl-anti-endo-3,4-methanopyrrolidine dicarboxylate (l-anti-endo-MPDC) blocked the uptake of [3H]d-aspartate, a non-metabolized substrate. Kinetic analysis demonstrated thatl-anti-endo-MPDC is a potent competitive inhibitor (Ki= 5μM) comparable to that ofl-glutamate andl-trans-2,4-pyrrolidine dicarboxylate (l-trans-2,4-PDC). Conformational analysis ofl-glutamate,l-trans-2,4-PDC andl-anti-endo-MPDC are used to refine the pharmacophore model of the transporter binding site.