Document Detail

The glycine site of the N-methyl-D-aspartate receptor channel: differences between the binding of HA-966 and of 7-chlorokynurenic acid.
MedLine Citation:
PMID:  1691278     Owner:  NLM     Status:  MEDLINE    
The mechanisms of action of three different glycine-site antagonists of the N-methyl-D-aspartate (NMDA)-receptor channel were analyzed employing [3H]glycine direct binding assays, as well as functional glycine- and glutamate-induced uncompetitive blocker binding assays. The latter assays measure apparent channel opening. All three antagonists tested, viz., 7-chlorokynurenic acid (7-Cl-KYNA), kynurenic acid (KYNA), and 1-hydroxy-3-aminopyrrolidone-2 (HA-966), inhibited the binding of [3H]glycine to the NMDA receptor in a dose-dependent manner. These antagonists also inhibited the glycine-induced increase in accessibility of the uncompetitive blocker [3H]N-[1-(2-thienyl)cyclohexyl]-piperidine ([3H]TCP) to the channel. 7-Cl-KYNA and KYNA, but not HA-966, completely blocked the glutamate-induced binding of [3H]TCP, in a manner similar to the non-competitive manner in which the selective NMDA antagonist D-(-)-2-amino-5-phosphonovaleric acid (AP-5) inhibited glycine-induced [3H]TCP binding. The inhibitory effects of HA-966 and of AP-5 on glutamate-induced [3H]TCP binding were overcome when glutamate concentrations were increased. Of the three antagonists, 7-Cl-KYNA appears to be the most potent (Ki = 0.4-1.0 microM) and the most selective glycine antagonist. KYNA was found to act at both the glycine (Ki = 40-50 microM) and the glutamate sites. In contrast, HA-966 (Ki = 6-17 microM) appears to act either on a domain distinct from the glutamate and the glycine sites, but tightly associated with the latter, or at the glycine site, but according to a mechanism distinct from that of 7-Cl-KYNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Y Kloog; H Lamdani-Itkin; M Sokolovsky
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  54     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  1990 May 
Date Detail:
Created Date:  1990-05-18     Completed Date:  1990-05-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1576-83     Citation Subset:  IM    
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
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MeSH Terms
Binding Sites / drug effects
Glycine / metabolism*
Ion Channels / metabolism*
Kynurenic Acid / analogs & derivatives*,  metabolism
Phencyclidine / analogs & derivatives,  metabolism
Pyrrolidinones / metabolism*
Rats, Inbred Strains
Receptors, N-Methyl-D-Aspartate
Receptors, Neurotransmitter / metabolism*
Strychnine / pharmacology
Grant Support
Reg. No./Substance:
0/Ion Channels; 0/Pyrrolidinones; 0/Receptors, N-Methyl-D-Aspartate; 0/Receptors, Neurotransmitter; 1003-51-6/HA 966; 18000-24-3/7-chlorokynurenic acid; 21500-98-1/1-(1-(2-thienyl)cyclohexyl)piperidine; 492-27-3/Kynurenic Acid; 56-40-6/Glycine; 57-24-9/Strychnine; 77-10-1/Phencyclidine

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