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

  • Bridges R
  • Lovering F
  • Koch H
 et al. 
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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.

Author-supplied keywords

  • Conformationally constrained
  • Excitatory amino acid
  • Glutamate
  • Inhibition
  • Transport

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Authors

  • Richard J. Bridges

  • Frank E. Lovering

  • Hans Koch

  • Carl W. Cotman

  • A. Richard Chamberlin

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