Abstract
Replacement of the methyl group of the AMPA receptor agonist 2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA) with a benzyl group provided the first AMPA receptor agonist, compound 7, capable of discriminating GluR2-4 from GluR1 by its more than 10-fold preference for the former receptor subtypes. An X-ray crystallographic analysis of this new analogue in complex with the GluR2-S1S2J construct shows that accommodation of the benzyl group creates a previously unobserved pocket in the receptor, which may explain the remarkable pharmacological profile of compound 7.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Brain / metabolism
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Cell Line
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Crystallography, X-Ray
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In Vitro Techniques
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Insecta
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Models, Molecular
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Molecular Sequence Data
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Patch-Clamp Techniques
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Radioligand Assay
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Rats
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Receptors, AMPA / agonists*
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Receptors, AMPA / chemistry
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Receptors, AMPA / physiology
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Stereoisomerism
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Structure-Activity Relationship
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Synaptosomes / metabolism
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Tetrazoles / chemical synthesis*
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Tetrazoles / chemistry
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Tetrazoles / pharmacology
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Xenopus laevis
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / analogs & derivatives*
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemical synthesis
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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2-amino-3-(3-hydroxy-5-(2-benzyl-2H-5-tetrazolyl)-4-isoxazolyl)propionic acid
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Receptors, AMPA
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Tetrazoles
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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glutamate receptor ionotropic, AMPA 2