A New Highly Selective Metabotropic Excitatory Amino Acid Agonist: 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric Acid

J Med Chem. 1996 Aug 2;39(16):3188-94. doi: 10.1021/jm9602569.

Abstract

The homologous series of acidic amino acids, ranging from aspartic acid (1) to 2-aminosuberic acid (5), and the corresponding series of 3-isoxazolol bioisosteres of these amino acids, ranging from (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA, 6) to (RS)-2-amino-6-(3-hydroxy-5-methylisoxazol-4-yl)hexanoic acid (10), were tested as ligands for metabotropic excitatory amino acid receptors (mGlu1 alpha, mGlu2, mGlu4a, and mGlu6). Whereas AMAA (6) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propinoic acid (AMPA, 7) are potent and highly selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively, the higher homologue of AMPA (7), (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (homo-AMPA, 8), is inactive at ionotropic excitatory amino acid receptors. Homo-AMPA (8), which is a 3-isoxazolol bioisostere of 2-aminoadipic acid (3), was, however, shown to be a specific and rather potent agonist at mGlu6, approximately 4 times weaker than the nonselective excitatory amino acid receptor agonist (S)-glutamic acid. 2-Aminoadipic acid (3), which shows a complex excitatory amino acid synaptic pharmacology, was an agonist at mGlu6 as well as mGlu2. AMPA (7) and the higher homologue of homo-AMPA (8), (RS)-2-amino-5-(3-hydroxy-5-methylisoxazol-4-yl)pentanoic acid (9), showed relatively weak agonist effects at mGlu6. It is concluded that homo-AMPA (8) is likely to be a useful tool for studies of the pharmacology and physiological role of mGlu6. We describe a new versatile synthesis of this homologue of AMPA and the synthesis of compound 10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives
  • Alanine / pharmacology
  • Animals
  • CHO Cells
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / chemical synthesis*
  • Excitatory Amino Acid Agonists / chemistry
  • Excitatory Amino Acid Agonists / metabolism
  • Excitatory Amino Acid Agonists / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • N-Methylaspartate / pharmacology
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism
  • 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 / chemistry
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology

Substances

  • 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid
  • Excitatory Amino Acid Agonists
  • Receptors, Metabotropic Glutamate
  • N-acetylalanyl-N-methylamide
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Alanine