Effects of RPR 118723, a novel antagonist at the glycine site of the NMDA receptor, in vitro (original) (raw)
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Antagonists and agonists at the glycine site of the NMDA receptor for therapeutic interventions
European Journal of Medicinal Chemistry, 2003
For decades neuroreceptor research has focused on the development of NMDA glycine-site antagonists, after Johnson and Ascher found out in 1987 about the co-agonistic character of this achiral amino acid at the NMDA receptor. Contrary to the inhibitory glycine receptor (glycine A ) the glycine binding site on the NMDA receptor (glycine B ) is strychnine-insensitive. A great diversity of diseases showing a disturbed glutamate neurotransmission have been linked to the NMDA receptor. Glycine site antagonists have been investigated for acute diseases like stroke and head trauma as well as chronic ones like dementia and chronic pain.
A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycine B ). All compounds displaced [ 3 H]MDL-105,519 binding to rat cortical membranes with IC 50 values of between 90 nM and 3.6 M. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 M, glycine 1 M) were antagonized by these same compounds with IC 50 values of 0.14 to 13.8 M. The antagonism observed was typical for glycine B antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher
A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycine B ). All compounds displaced [ 3 H]MDL-105,519 binding to rat cortical membranes with IC 50 values of between 90 nM and 3.6 M. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 M, glycine 1 M) were antagonized by these same compounds with IC 50 values of 0.14 to 13.8 M. The antagonism observed was typical for glycine B antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher
British Journal of Pharmacology, 2000
The potency of two novel glycine site antagonists, GV150,526A and GV196,771A, was assessed by their ability to inhibit the binding of [3H]‐MDL105,519 to cell homogenates prepared from mammalian cells transfected with either NR1‐1a, NR1‐2a, NR1‐1a/NR2A, NR1‐1a/NR2B, NR1‐1a/NR2C or NR1‐1a/NR2D NMDA receptor clones. The inhibition constants (Kis) for GV150,526A displacement of [3H]‐MDL105,519 binding to either NR1‐1a or NR1‐2a expressed alone were not significantly different and were best fit by a one‐site binding model. GV150,526A inhibition to NR1‐1a/NR2 combinations was best fit by a two‐site model with the NR1‐1a/NR2C having an approximate 2–4 fold lower affinity compared to other NR1‐1a/NR2 receptors. The Kis for GV196,771A displacement of [3H]‐MDL105,519 binding to NR1‐1a, NR1‐2a and all NR1‐1a/NR2 combinations was best fit by a two‐site binding model. There was no significant difference between the Kis for the binding to NR1‐1a and NR1‐2a; NR1‐1a/NR2A receptors had an approximat...
In vitro and in vivo antagonistic activities of SM31900 for the NMDA receptor glycine-binding site
Brain Research, 2002
The purpose of this study was to clarify the in vitro pharmacological profile and the in vivo activity of (3S)-7-chloro-3-[2-((1R)-1carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1, 3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-3 3 31900). SM-31900 inhibited the binding of [ H]glycine and [ H]5,7-dichlorokynurenic acid, radioligands for the N-methyl-D-aspartate (NMDA) receptor glycine-binding site, to rat brain membranes in a competitive manner, with K values of 1162 and 1.060.1 nM, i 3
Activation of the glycine site in the NMDA receptor is necessary for the induction of LTP
Neuroscience Letters, 1990
The effects of 7-chlorokynurenate (7-C1KY) were examined on N-methyl-D-aspartate (NMDA) receptor-mediated synaptic mechanisms in the CAI region of rat hippocampal slices. 7-CIKY depressed both the NMDA receptor-mediated component of synaptic transmission recorded in Mg2÷-free medium and the induction of long-term potentiation (LTP) in Mg2+-containing medium. Both of these effects were reversed by D-serine, suggesting that the action of 7-CIKY was at the allosteric glycine site on the NMDA receptor.
Neuropharmacology, 1997
The pharmacological effects of two novel N-methyl-D-aspartate (NMDA) receptor glycine site antagonists, L-701,324 and L-695,902 were examined on whole-cell voltage-clamped cells and compared to a prototypic antagonist, 7-chlorokynurenic acid. Both L-701,324 and L-695,902 non-competitively antagonised NMDA responses elicited in rat cultured cortical neurones, this was shown to be due to a competitive interaction at the glycine co-agonist site on the receptor complex (Kb values: 19 nM and 2.6 PM, respectively). Inhibition curves for the antagonism of responses to combined applications of NMDA and glycine showed that both antagonists were devoid of any intrinsic activity i.e. "full" antagonists and were, therefore, capable of completely abolishing inward currents. Despite this fact, both of these novel antagonists apparently modulated glutamate affinity for its recognition site-a property hitherto associated only with glycine site partial agonists. Human recombinant NMDA receptors comprising NRla/NR2A and NRla/NR2B subunits expressed in mouse fibroblast cells were also used to determine whether L-701,324 and L-695,902 were capable of discriminating between subtypes of NMDA receptor. Inhibition curves to each antagonist showed no difference in affinity for either of these subunit assemblies (mKr values: L-701,324 = 0.005 PM on both assemblies; L-695,902 = 4.37 and 3.7 PM on NRla/NR2A and NRla/NR2B, respectively). Kinetic analysis of the off-rates of antagonism with L-701,324 revealed that the high affinity of this compound compared to 7-chlorokynurenic acid were attributable to an exceptionally slow dissociation of the antagonist from the receptor. Copyright 0 1996
Glycine site associated with the NMDA receptor modulates long-term potentiation
Synapse, 1990
Recent work has shown that kynurenic acid and several quinoxaline derivatives act as non-competitive NMDA receptor antagonists by binding to the glycine site associated with this receptor. In this study, we have tested the effect of the most potent and selective of these compounds, 7-chlorokynurenic acid (C1-Kyn), on the induction of long-term potentiation, an event know to involve activation of NMDA receptors. It was found that 30 m̈M C1-Kyn reversibly abolished the development of both short-term and long-term potentiation in the CA1 region of hippocampal slices. The effectiveness of C1-Kyn matched its ability to inhibit 3H-glycine binding and the association of 3H-TCP with the NDMA receptor in binding experiments (Ki 0.7–1 μM). Weak interactions of C1-Kyn with AMPA receptor sites were observed and may account for a partial, reversible reduction in the epsp. However, blockade of long-term potentiation by C1-Kyn was completely reversed by simultaneous application of the glycine site agonist D-serine and thus must be attributed to its interaction with the glycine site. These results indicate that the glycine site coupled to the NMDA receptor potently modulates channel function during physiological events related to synaptic activation.
British Journal of Pharmacology, 1998
1 N-methyl-D-aspartic acid (NMDA) receptors are known to play a key role in the induction phase of long-term potentiation (LTP) at certain hippocampal synapses and to represent some component of spatial learning in animals. The ability of NMDA receptor antagonists (or gene knockout) to impair LTP has led to the suggestion that the therapeutic use of such antagonists may impair cognitive function in humans. The present study compares the eects on LTP of NMDA receptor ion channel block by MK-801 and glycine-site antagonism by 3R(+)cis-4-methyl-pyrrollid-2-one (L-687,414). 2 In vitro experiments using rat cortical slices revealed L-687,414 to be *3.6 fold more potent than its parent analogue, R(+)HA-966 at antagonizing NMDA-evoked population depolarizations (apparent K b s: 15 mM and 55 mM, respectively). 3 Whole-cell voltage-clamp experiments using rat cultured cortical neurones revealed L-687,414 to shift to the right the concentration-response relationship for NMDA-evoked inward current responses (pK b =6.2+0.12). L-687,414 anity for the glycine site on the NMDA receptor complex was also determined from concentration-inhibition curves, pKi=6.1+0.09. In the latter experiments, L-687,414 and R(+)HA-966 were unable to completely abolish inward current responses suggesting each compound to be a low ecacy partial agonist (estimated intrinsic activity=*10 and 20% of glycine, respectively). 4 L-687,414 and MK-801 were compared for their eects on NMDA receptor-dependent LTP in the dentate gyrus of anaethestized rats following high frequency stimulation of the medial perforant path (mPP) aerents. Control rats, administered saline (0.4 ml kg 71 followed by 0.0298 ml min 71 ), showed a robust augmentation of the population e.p.s.p. risetime (LTP) recorded in the dentate hilus following tetanic stimulation of the mPP. LTP was eectively abolished in a separate group of rats treated with an MK-801 dosing regimen (0.12 mg kg 71 i.v. followed by 1.8 mg kg 71 h 71 ) known to produce maximal neuroprotection in a rat stroke model but, by contrast, remained largely intact in a third group of animals given a similarly neuroprotective L-687,414 treatment (28 mg kg 71 i.v. followed by 28 mg kg 71 h 71 ). 5 These experiments suggest that a low level of intrinsic activity at the glycine site may be sucient to support NMDA receptor-dependent LTP but in circumstances where there is likely to be an excessive NMDA receptor activation the agonism associated with a low ecacy partial agonist, such as L-687,414, is dominated by the antagonist properties. Thus, an NMDA receptor partial agonist pro®le may oer a therapeutic advantage over neutral antagonists by permitting an acceptable level of`normal' synaptic transmission whilst curtailing excessive receptor activation.