Synthesis, binding affinity at glutamic acid receptors, neuroprotective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids

J Med Chem. 2005 Oct 6;48(20):6315-25. doi: 10.1021/jm0504499.

Abstract

The four stereoisomers of 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid(+)-4, (-)-4, (+)-5, and (-)-5 were prepared by stereoselective synthesis of two pairs of enantiomers, which were subsequently resolved by enzymatic procedures. These four stereoisomers and the four stereoisomers of the bicyclic analogue 5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid (+)-2, (-)-2, (+)-3, and (-)-3 were tested at ionotropic and metabotropic glutamate receptor subtypes. The most potent NMDA receptor antagonists [(+)-2, (-)-4, and (+)-5] showed a significant neuroprotective effect when tested in an oxygen glucose deprivation (OGD) cell culture test. The same compounds were preliminarily assayed using Xenopus oocytes expressing cloned rat NMDA receptors containing the NR1 subunit in combination with either NR2A, NR2B, NR2C, or NR2D subunit. In this assay, all three derivatives showed high antagonist potency with preference for the NR2A and NR2B subtypes, with derivative (-)-4 behaving as the most potent antagonist. The biological data are discussed on the basis of homology models reported in the literature for NMDA receptors and mGluRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / pharmacology
  • Animals
  • Binding Sites
  • CHO Cells
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Cricetulus
  • Female
  • In Vitro Techniques
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Mice
  • Models, Molecular
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Oocytes / drug effects
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Glutamate / drug effects
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism*
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Second Messenger Systems / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • Amino Acids
  • Isoxazoles
  • NR2A NMDA receptor
  • Neuroprotective Agents
  • Protein Subunits
  • Receptors, Glutamate
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • metabotropic glutamate receptor 2