A CONFORMATIONALLY CONSTRAINED COMPETITIVE INHIBITOR OF THE SODIUM-DEPENDENT GLUTAMATE TRANSPORTER IN FOREBRAIN SYNAPTOSOMES - L-ANTI-ENDO-3,4-METHANOPYRROLIDINE DICARBOXYLATE

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 [H-3]D-aspartate, a non-metabolized substrate. Kinetic analysis demonstrated that L-anti-endo-MPDC is a potent competitive inhibitor (K-i = 5 mu M) 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.