Potent indole- and quinoline-containing N-methyl-D-aspartate antagonists acting at the strychnine-insensitive glycine binding site.
The N-methyl-D-aspartate (NMDA)-preferring glutamate receptor subtype possesses, in addition to the recognition site for glutamate, a binding site for glycine. We report here on the pharmacological properties of 3-(4,6-dichloro-2-carboxyindol-3-yl)-propionic acid (MDL 29,951) and 4-carboxymethylamino-5,7-dichloroquinoline-2-carboxylic acid (MDL 100,748), two novel glycine antagonists of NMDA receptor activation in vitro and in vivo. We have measured in parallel the effects of two previously described glycine antagonists, 7-chlorokynurenic acid and 5,7-dichlorokynurenic acid. All were potent inhibitors of [3H]glycine binding. Ki values (microM) were 0.36 (7-chlorokynurenic acid), 0.08 (5,7-dichlorokynurenic acid), 0.07 (MDL 100,748) and 0.14 (MDL 29,951). MDL 100,748 and MDL 29,951 were approximately 2000-fold selective for the glycine binding site relative to the glutamate recognition sites. All four compounds completely inhibited the use-dependent binding of [3H]N-[1-(2-thienyl) cyclohexyl]-piperidine and were noncompetitive, glycine-reversible inhibitors of both NMDA-induced biochemical and electrophysiological responses in brain slice preparations. A competitive interaction with the glycine binding site was also evident in that MDL 29,951 and MDL 100,748 produced parallel rightward shifts in the glycine requirement for demonstration of NMDA-stimulated elevations in cytosolic calcium in cultured neuronal preparations. The glycine antagonists were potent anticonvulsants after their i.c.v. administration to audiogenic seizure-susceptible DBA/2J mice. Because the compounds chosen encompass a variety of chemical structures, the results indicate that glycine is required for NMDA receptor activation and that bioavailable glycine antagonists may form the basis of a novel therapy for epilepsy.
Baron
B M
BM
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Harrison
B L
BL
McDonald
I A
IA
Meldrum
B S
BS
Palfreyman
M G
MG
Salituro
F G
FG
Siegel
B W
BW
Slone
A L
AL
Turner
J P
JP
White
H S
HS
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011422:Propionates / Q000378:metabolism / Q000627:therapeutic use*; D011804:Quinolines / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control; D013331:Strychnine / Q000378:metabolism
C000588735:2-carboxy-4,6-dichloro-(1H)-indole-3-propanoic acid; D000927:Anticonvulsants; D007211:Indoles; D011422:Propionates; D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; C066613:MDL 100748; D013331:Strychnine; D002118:Calcium; D005998:Glycine