(3SR,4aRS,6SR,8aRS)-6-(1H-tetrazol-5-yl)decahydroisoquinoline-3-carboxylic acid, a novel, competitive, systemically active NMDA and AMPA receptor antagonist

J Med Chem. 1995 Dec 8;38(25):4885-90. doi: 10.1021/jm00025a005.

Abstract

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole-substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtained from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.

MeSH terms

  • Animals
  • Binding, Competitive
  • Columbidae
  • Excitatory Amino Acid Antagonists / chemical synthesis*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology
  • Mice
  • Molecular Structure
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, Kainic Acid / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / pharmacology

Substances

  • Excitatory Amino Acid Antagonists
  • Isoquinolines
  • LY 246492
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Tetrazoles