3-(2-Carboxyindol-3-yl)propionic Acid-Based Antagonists of the N-methyl-D-aspartic Acid Receptor Associated Glycine Binding Site

J Med Chem. 1992 May 15;35(10):1791-9. doi: 10.1021/jm00088a014.

Abstract

A series of substituted 3-(2-carboxyindol-3-yl)propionic acids was synthesized and tested as antagonists for the strychnine-insensitive glycine binding site of the NMDA receptor. Chlorine, and other small electron-withdrawing substituents in the 4- and 6-positions of the indole ring, greatly enhanced binding and selectivity for the glycine site over the glutamate site of the NMDA receptor; one of the most potent compounds is 3-(4,6-dichloro-2-carboxyindol-3-yl)propionic acid (IC50 = 170 nM; greater than 2100-fold selective for glycine). The importance of a heteroatom NH and the enhancing effect of the propionic acid side chain were demonstrated and are consistent with previous results which suggest the presence of a pocket on the receptor which can accept an acidic side chain. Substitution of a sulfur at C3 led to the most potent compound 3-[(carboxymethyl)thio]-2-carboxy-4,6-dichloroindole (IC50 = 100 nM).

MeSH terms

  • Animals
  • Binding Sites
  • Cerebral Cortex / metabolism
  • Glycine / metabolism*
  • Hippocampus / metabolism
  • Indoles / pharmacology*
  • Mice
  • Mice, Inbred DBA
  • Propionates / pharmacology*
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Seizures / prevention & control
  • Structure-Activity Relationship
  • Strychnine / pharmacology
  • Substrate Specificity

Substances

  • Indoles
  • Propionates
  • Receptors, N-Methyl-D-Aspartate
  • 3-(2-carboxyindol-3-yl)propionic acid
  • Strychnine
  • Glycine