A conformationally constrained competitive inhibitor of the sodium-dependent glutamate transporter in forebrain synaptosomes: l-anti-endo-3,4-methanopyrrolidine dicarboxylate

Abstract

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 μM) 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. © 1994.