Bridges R J, Lovering F E, Koch H, Cotman C W, Chamberlin A R
Department of Pharmaceutical Sciences, University of Montana, Missoula 59812.
Neurosci Lett. 1994 Jun 20;174(2):193-7. doi: 10.1016/0304-3940(94)90019-1.
A series of L-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, only L-anti-endo-3,4-methanopyrrolidine dicarboxylate (L-anti-endo-MPDC) blocked the uptake of [3H]D-aspartate, a non-metabolized substrate. Kinetic analysis demonstrated that L-anti-endo-MPDC is a potent competitive inhibitor (Ki = 5 microM) comparable to that of L-glutamate and L-trans-2,4-pyrrolidine dicarboxylate (L-trans-2,4-PDC). Conformational analysis of L-glutamate, L-trans-2,4-PDC and L-anti-endo-MPDC are used to refine the pharmacophore model of the transporter binding site.
研究了一系列L-3,4-亚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体的潜在抑制剂。在所测试的异构体中，只有L-反式-内型-3,4-亚甲基吡咯烷二羧酸酯（L-反式-内型-MPDC）阻断了[3H]D-天冬氨酸（一种非代谢底物）的摄取。动力学分析表明，L-反式-内型-MPDC是一种强效竞争性抑制剂（Ki = 5 microM），与L-谷氨酸和L-反式-2,4-吡咯烷二羧酸酯（L-反式-2,4-PDC）相当。利用L-谷氨酸、L-反式-2,4-PDC和L-反式-内型-MPDC的构象分析来完善转运体结合位点的药效团模型。
