3-(2-Carboxyindol-3-yl)propionic acid-based antagonists of the N-methyl-D-aspartic acid receptor associated glycine binding site.
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).
Salituro
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FG
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Harrison
B L
BL
Baron
B M
BM
Nyce
P L
PL
Stewart
K T
KT
Kehne
J H
JH
White
H S
HS
McDonald
I A
IA
D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D005998:Glycine / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000494:pharmacology; D013379:Substrate Specificity
D007211:Indoles; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; C066275:3-(2-carboxyindol-3-yl)propionic acid; D013331:Strychnine; D005998:Glycine