Efficacy and safety of glycine site agonists of the N-methyl-D-aspartate receptor in schizophrenia treatment

2000 ◽  
Vol 10 ◽  
pp. 212
Author(s):  
U. Heresco-Levy
Keyword(s):  
Efficacy And Safety ◽  
Glycine Site ◽  
Aspartate Receptor

scholarly journals Reversal of Phencyclidine-Induced Dopaminergic Dysregulation by N-Methyl-D-Aspartate Receptor/Glycine-site Agonists

2003 ◽  
Vol 29 (2) ◽  
pp. 300-307 ◽  
Author(s):  
Daniel C Javitt ◽  
Andrea Balla ◽  
Sarah Burch ◽  
Ray Suckow ◽  
Shan Xie ◽  
...  
Keyword(s):  
Glycine Site ◽  
Aspartate Receptor

scholarly journals Expression and characterization of a glycine-binding fragment of the N-methyl-D-aspartate receptor subunit NR1

1999 ◽  
Vol 340 (3) ◽  
pp. 687-692 ◽  
Author(s):  
Jun-ichi MIYAZAKI ◽  
Shigetada NAKANISHI ◽  
Hisato JINGAMI
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Full Length ◽  
Soluble Form ◽  
Soluble Receptor ◽  
Glycine Site ◽  
Binding Characteristics ◽  
Aspartate Receptor ◽  
Extracellular Region ◽  
Membrane Bound

N-Methyl-D-aspartate receptor channels are composed of an NR1 subunit and at least one of the NR2 subunits (NR2A-D). Activation of the N-methyl-D-aspartate receptor requires the co-agonists glycine and glutamate. It has been proposed that the NR1 subunit possesses a glycine-binding site. We have expressed a soluble form of the NR1 subunit, which was produced by connecting the N-terminal extracellular region with the extracellular loop between the third and fourth membrane segments, by a baculovirus system along with full-length and truncated membrane-bound forms. The soluble NR1 receptor was efficiently secreted into the culture medium and showed a high affinity for ligands. The Kd of a glycine-site antagonist, [3H]MDL 105,519 [(E)-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1H-indole-2-carboxylic acid], for the soluble receptor was 3.89±0.97 nM, which was comparable to the Kd of 4.47±1.39 nM for the membrane-bound full-length form. These values were close to the values reported previously with the use of rat brain membranes and Chinese hamster ovary cells expressing the full-length form of the NR1 subunit. The Ki values of other glycine-site antagonists, L-689,560 (trans-2-carboxy-5,7-dichloro - 4 - phenylaminocarbonylamino - 1,2,3,4 - tetrahydroquinoline), 5,7-dichlorokynurenate and 5,7-dinitroquinoxaline-2,3-dione, for the soluble receptor were also similar to those for the full-length form of NR1. [3H]MDL 105,519 binding was also inhibited by the agonists glycine and D-serine. Thus the affinity and selectivity of ligand-binding characteristics of the NR1 subunit is conferred on the soluble form of the NR1 subunit. This soluble receptor provides a good experimental tool for initiating a biophysical analysis of the N-methyl-D-aspartate receptor channel protein.

Stereoselectivity for the (R)-Enantiomer of HA-966 (l-Hydroxy-3-Aminopyrrolidone-2) at the Glycine Site of the N-Methyl-d-Aspartate Receptor Complex

1990 ◽  
Vol 55 (4) ◽  
pp. 1346-1351 ◽  
Author(s):  
L. M. Pullan ◽  
M. Britt ◽  
M. J. Chapdelaine ◽  
R. A. Keith ◽  
D. LaMonte ◽  
...  
Keyword(s):  
Receptor Complex ◽  
Glycine Site ◽  
Aspartate Receptor

scholarly journals D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor

2000 ◽  
Vol 97 (9) ◽  
pp. 4926-4931 ◽  
Author(s):  
J.-P. Mothet ◽  
A. T. Parent ◽  
H. Wolosker ◽  
R. O. Brady ◽  
D. J. Linden ◽  
...  
Keyword(s):  
Glycine Site ◽  
Endogenous Ligand ◽  
Aspartate Receptor

Efficacy of N-methyl-D-aspartate receptor modulator augmentation in schizophrenia: A meta-analysis of randomised, placebo-controlled trials

2021 ◽  
pp. 026988112096593
Author(s):  
Kah Kheng Goh ◽  
Tzu-Hua Wu ◽  
Chun-Hsin Chen ◽  
Mong-Liang Lu
Keyword(s):  
Negative Symptoms ◽  
Primary Outcome ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Efficacy And Safety ◽  
Receptor Modulator ◽  
Aspartate Receptor ◽  
Double Blinded ◽  
Receptor Modulators ◽  
Positive And Negative Symptoms

Background: Dysfunction of the N-methyl- D-aspartate glutamate receptor is involved in the putative pathology of schizophrenia. There is growing interest in the potential of N-methyl- D-aspartate receptor modulators to improve the symptoms of schizophrenia, but the evidence for the use of glutamatergic agents for augmenting schizophrenia remains inconclusive. Aims: We conducted a meta-analysis to test the efficacy and safety of N-methyl- D-aspartate receptor modulator supplements in patients with schizophrenia. Methods: Following a systemic search in MEDLINE, Embase, Cochrane and Scopus, 40 double-blinded, randomised, placebo-controlled trials involving 4937 patients with schizophrenia were included in this meta-analysis. The change in the severity of symptoms among patients with schizophrenia was defined as the primary outcome, whereas the safety profiles of the intervention, including the discontinuation rate and adverse events, were defined as secondary outcomes. Results: When added to antipsychotic treatments, N-methyl- D-aspartate receptor modulators improved multiple schizophrenia symptoms, particularly negative symptoms, and had satisfactory side effects and safety profile. Among the seven glutamatergic agents analysed, glycine, D-serine and sarcosine had better treatment profiles than other agents, and NMDA receptor co-agonists, as a group, provided a reduction in schizophrenia symptoms compared to antipsychotic treatments without supplementation. Augmentation with N-methyl- D-aspartate receptor modulators was only effective among patients treated with antipsychotics other than clozapine. Conclusions: The results indicate that N-methyl- D-aspartate receptor modulators, particularly with glycine, D-serine and sarcosine, are more beneficial than the placebo in treating schizophrenia, and the effects extended to both positive and negative symptoms, when augmented with antipsychotics other than clozapine.

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