3-(2-Carboxyindol-3-yl)propionic acid-based antagonists of the NMDA (N-methyl-D-aspartic acid) receptor associated glycine binding site

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).