The substituted aspartate analogue L-β-threo-benzyl-aspartate preferentially inhibits the neuronal excitatory amino acid transporter EAAT3

C. Sean Esslinger, Shailesh Agarwal, John Gerdes, Paul A. Wilson, Erin S. Davis, Alicia N. Awes, Erin O'Brien, Teri Mavencamp, Hans P. Koch, David J. Poulsen, Joseph F. Rhoderick, A. Richard Chamberlin, Michael P. Kavanaugh, Richard J. Bridges

Research output: Contribution to journalArticlepeer-review

Abstract

The excitatory amino acid transporters (EAATs) play key roles in the regulation of CNS L-glutamate, especially related to synthesis, signal termination, synaptic spillover, and excitotoxic protection. Inhibitors available to delineate EAAT pharmacology and function are essentially limited to those that non-selectively block all EAATs or those that exhibit a substantial preference for EAAT2. Thus, it is difficult to selectively study the other subtypes, particularly EAAT1 and EAAT3. Structure activity studies on a series of β-substituted aspartate analogues identify L-β-benzyl-aspartate (L-β-BA) as among the first blockers that potently and preferentially inhibits the neuronal EAAT3 subtype. Kinetic analysis of D-[3H] aspartate uptake into C17.2 cells expressing the hEAATs demonstrate that L-β-threo-BA is the more potent diastereomer, acts competitively, and exhibits a 10-fold preference for EAAT3 compared to EAAT1 and EAAT2. Electrophysiological recordings of EAAT-mediated currents in Xenopus oocytes identify L-β-BA as a non-substrate inhibitor. Analyzing L-β-threo-BA within the context of a novel EAAT2 pharmacophore model suggests: (1) a highly conserved positioning of the electrostatic carboxyl and amino groups; (2) nearby regions that accommodate select structural modifications (cyclopropyl rings, methyl groups, oxygen atoms); and (3) a unique region L-β-threo-BA occupied by the benzyl moieties of L-TBOA, L-β-threo-BA and related analogues. It is plausible that the preference of L-β-threo-BA and L-TBOA for EAAT3 and EAAT2, respectively, could reside in the latter two pharmacophore regions.

Original languageEnglish
Pages (from-to)850-861
Number of pages12
JournalNeuropharmacology
Volume49
Issue number6
DOIs
StatePublished - Nov 2005

Keywords

  • Glutamate uptake
  • Molecular modeling
  • Neurotransmitter transporter
  • Pharmacophore model
  • Transport inhibitors

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