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 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Transport System X-AG
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Animals
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Aspartic Acid / metabolism
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Binding Sites
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Biological Transport / physiology
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Dicarboxylic Acids / chemistry
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Dicarboxylic Acids / pharmacokinetics
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Dicarboxylic Acids / pharmacology*
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Glycoproteins / antagonists & inhibitors*
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In Vitro Techniques
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Kinetics
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Male
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Molecular Conformation
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Prosencephalon / metabolism*
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Prosencephalon / ultrastructure
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Protein Binding
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Sodium / physiology*
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Synaptosomes / metabolism*
Substances
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3,4-methanopyrrolidine dicarboxylate
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Amino Acid Transport System X-AG
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Dicarboxylic Acids
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Glycoproteins
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Pyrrolidines
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Aspartic Acid
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Sodium