Abstract
The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter and more convergent synthetic route than previously described, employing a new method for introducing the amino acid moiety, was developed for these derivatives. The 2-substituted isomers were selective agonists, and their activity correlated inversely with the size of the substituent. Structural explanations of the structure-activity relationship are provided.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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In Vitro Techniques
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Models, Molecular
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Radioligand Assay
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Rats
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Receptors, AMPA / agonists*
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Receptors, AMPA / metabolism*
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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 / pharmacology
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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 / pharmacology
Substances
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Receptors, AMPA
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Tetrazoles
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid