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. doi: 10.1021/jm050014l.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • In Vitro Techniques
  • Models, Molecular
  • Radioligand Assay
  • Rats
  • Receptors, AMPA / agonists*
  • Receptors, AMPA / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Synaptosomes / metabolism
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / pharmacology
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / analogs & derivatives*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemical synthesis*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

  • Receptors, AMPA
  • Tetrazoles
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid