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

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 t...

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Published in:	Neuropharmacology Vol. 49; no. 6; pp. 850 - 861
Main Authors:	Esslinger, C. Sean, Agarwal, Shailesh, Gerdes, John, Wilson, Paul A., Davis, Erin S., Awes, Alicia N., O'Brien, Erin, Mavencamp, Teri, Koch, Hans P., Poulsen, David J., Rhoderick, Joseph F., Chamberlin, A. Richard, Kavanaugh, Michael P., Bridges, Richard J.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-11-2005
Subjects:	Amino Acid Transport System X-AG - antagonists & inhibitors Animals Aspartic Acid - analogs & derivatives Aspartic Acid - chemistry Aspartic Acid - pharmacology Cell Line, Transformed Dose-Response Relationship, Drug Electric Stimulation - methods Excitatory Amino Acid Transporter 1 - physiology Excitatory Amino Acid Transporter 2 - physiology Excitatory Amino Acid Transporter 3 - antagonists & inhibitors Excitatory Amino Acid Transporter 3 - physiology Gene Expression - drug effects Gene Expression - physiology Glutamate uptake Membrane Potentials - drug effects Membrane Potentials - physiology Membrane Potentials - radiation effects Mice Models, Molecular Molecular modeling Neurons - drug effects Neurons - metabolism Neurotransmitter transporter Oocytes Patch-Clamp Techniques - methods Pharmacophore model Transfection - methods Transport inhibitors Tritium - pharmacokinetics Xenopus Transport inhibitors Glutamate uptake Pharmacophore model Molecular modeling Neurotransmitter transporter
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-3908 1873-7064
DOI:	10.1016/j.neuropharm.2005.08.009