RT Journal Article
SR Electronic
T1 Potent indole- and quinoline-containing N-methyl-D-aspartate antagonists acting at the strychnine-insensitive glycine binding site.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 947
OP 956
VO 262
IS 3
A1 B M Baron
A1 B L Harrison
A1 I A McDonald
A1 B S Meldrum
A1 M G Palfreyman
A1 F G Salituro
A1 B W Siegel
A1 A L Slone
A1 J P Turner
A1 H S White
YR 1992
UL http://jpet.aspetjournals.org/content/262/3/947.abstract
AB 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.