Convergent synthesis and pharmacology of substituted tetrazolyl-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid analogues.

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Vogensen SB, Clausen RP, Greenwood JR, Johansen TN, Pickering DS, Nielsen B, Ebert B, Krogsgaard-Larsen P

Convergent synthesis and pharmacology of substituted tetrazolyl-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid analogues.

J Med Chem. 2005 May 5;48(9):3438-42.

PubMed ID

15857151 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(S)-AMPA	Glutamate receptor 2	Ki (nM)	16.8	N/A	N/A	Details