Selective block of recombinant glur6 receptors by NS-102, a novel non-NMDA receptor antagonist

Verdoorn, Todd A.; Johansen, Tina H.; Drejer, Jørgen; Nielsen, Elsebet Ø.

doi:10.1016/0922-4106(94)90024-8

Cited by 117 publications

(56 citation statements)

References 16 publications

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“…By comparing the inhibitory effects of the two compounds, it is possible to distinguish between the activity of kainate receptors and AMPA receptors (Sheardown et al, 1990). Recently,a new compound,7,8,9,tetrahydrobenzo[g]indole-2,3-dione-3-oxime (NS-102), was used as a specific competitive antagonist of low affinity kainate receptors (Johansen et al, 1993;Verdoorn et al, 1994). Also, a new non-competitive and specific inhibitor of AMPA receptors, GYKI 53655, is a useful tool to distinguish between the activity of AMPA and kainate receptors, since kainate receptors are insensitive to this compound (Partenain et al, 1995).…”

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confidence: 99%

Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

Malva

Carvalho

1998

Neurochemistry International

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The hippocampal CA3 subregion of the rat is characteristically enriched in kainate receptors. At the synaptic level, the subcellular localization of these receptors is still a matter of debate. The CA3 pyramidal cells are particularly sensitive to excitotoxicity induced by kainate, which is in agreement with the high levels of kainate receptors in the stratum lucidum of the hippocampal CA3 subregion. Immunocytochemical studies, using antibodies against kainate receptor subunits, clearly demonstrated the presence of postsynaptic kainate receptors. However, it was not possible at the time to identify the activity of postsynaptic kainate receptors as mediators of the synaptic transmission. There are also reports showing the labeling of unmyelinated axons and nerve terminals with antibodies against kainate receptor subunits. The evidence for the presence of presynaptic kainate receptors in the hippocampus is further substantiated by the demonstration that stimulation of kainate receptors in synaptosomes isolated from the rat hippocampal CA3 subregion increases the intracellular free Ca 2÷ concentration ([Ca2+]~) coupled to the release of glutamate. These results support the model proposed by Coyle (1983), in which the excitotoxicity induced by kainate involves the activation of presynaptic kainate receptors, causing the release of glutamate. According to this model, the neurotoxic effect of kainate in the rat hippocampal CA3 subregion involves a direct effect on presynaptic kainate receptors and an indirect effect on postsynaptic glutamate receptors due to the enhanced release of glutamate.

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confidence: 99%

Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

Malva

Carvalho

1998

Neurochemistry International

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“…Oxime 5.1 (NS102) has been reported to be a selective GluK2 antagonist with little effect on GluA2/GluA4 receptors (65). However, 5.1 has also been shown to block GluK1-containing KA receptors on DRG neurons with weaker effects at native AMPA receptors expressed in the cortex (Table 5) (49).…”

Section: Isatinoxime Derivativesmentioning

confidence: 99%

Medicinal Chemistry of Competitive Kainate Receptor Antagonists

Larsen

Bunch

2010

ACS Chem. Neurosci.

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Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field.Keywords: Glutamate receptors, kainic acid receptors, competitive antagonists, medicinal chemistry, structureactivity relationship studies T he common R-amino acid (S)-glutamate (Glu) functions as the major endogenous excitatory neurotransmitter in the central nervous system (CNS). Upon its release into the synaptic cleft, it activates the Glu receptors. These receptors have been divided into two major classes: the ligand-gated ion channels named the ionotropic receptors (iGluRs) and the slower acting G-protein coupled receptors named the metabotropic receptors (mGluRs). On the basis of ligand affinity studies, the class of iGluRs has been divided into three subgroups: the N-methyl-D-aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and kainate (KA) receptors (1-3). With focus on the KA receptors, it is believed that this subgroup of receptors are potential therapeutic targets in diseases such as schizophrenia, major depression, pain, and epilepsy. In order to elucidate the role of the KA receptors, medicinal chemists have attempted to develop subtype-selective KA receptor ligands for the last two to three decades. Although extensive effort has been made, only a limited number of subtype-selective KA receptor ligands have been reported. For a comprehensive review on KA receptor agonists, see our recent review (4). The aim of this review is to provide the medicinal chemists (and others) who have an interest in the structure-activity relationship (SAR) of competitive KAR antagonists with an overview of the field. This information may aid the design of new subunit-selective KA receptor antagonists.

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“…Such a similar slight inhibition suggests that the responses to KA and AMPA are induced by the same receptors. Verdoorn et al (1994) reported that 42·1 ± 6·4 and 9·6 ± 5·2 % of the KA-induced currents mediated by GluR-6 and GluR-BÏD expressed in fibroblasts were blocked by 3 ² 10¦É Ò NS-102, respectively. The percentage inhibition of the KA and AMPA responses in the dissociated Meynert neurones in the present study was very close to the inhibition of GluR-BÏD, thus indicating that the Meynert neurones do not have KA receptors but AMPA receptors.…”

Section: Ka and Ampa Responsesmentioning

confidence: 99%

Age‐related functional changes of the glutamate receptor channels in rat Meynert neurones

Akaike

Rhee

1997

The Journal of Physiology

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The developmental changes of glutamate receptors (GluRs) in acutely dissociated rat Meynert neurones were investigated using the conventional whole‐cell and nystatin perforated patch recording modes under voltage‐clamp conditions. The neurones became less responsive to N‐methyl‐d‐aspartic acid (NMDA) with age, most dramatically between 1 day and 2 weeks, while the responses to kainic acid (KA) and l‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) gradually increased. The metabotropic GluR response appeared a few days after birth, but thereafter no further change was observed. The decrease in the NMDA response during postnatal development was due to an abrupt reduction in the number of receptors without affecting the affinity, voltage‐dependent Mg2+ blockade or high Ca2+ permeability (Pca/PCs≈ 7.0). P ca/PCs in the presence of KA decreased from 2.8 in the 1‐day‐old (1D) rat neurones to 1.1 and 0.44 in the 2‐week‐old (2W) and 6‐month‐old (6M) rat neurones, respectively. The concentration–response relationship for KA shifted to the left with age. The KA response was not affected by NS‐102, a KA‐selective antagonist, thus indicating that the increased affinity of the receptor for the ligand resulted from the change in the AMPA receptor channel subunits. The AMPA response in the presence of 10−4 M cyclothiazide showed a change in the inward rectifying current–voltage relationship with age. The KA response was strongly cross‐desensitized by the addition of AMPA and was also blocked by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), whereas a rapid desensitization of the AMPA response was removed in a concentration‐dependent manner by cyclothiazide. These results indicate that the non‐NMDA receptor channels are assembled from the subunits of the AMPA receptor family without the GluR‐2 subunit, thus resulting in a high Ca2+ permeability. The l‐glutamate (Glu)‐induced responses were more sensitive to dl‐2‐amino‐5‐phosphonopentanoic acid (APV) in the 1D rat neurones than in the adult rat neurones. Both NMDA and KA raised the intracellular Ca2+ concentration ([Ca2+]i) in all neurones of 1D, 2W and 6M rats, though the charybdotoxin‐sensitive Ca2+‐activated K+ current (IK(ca)) did not appear in the 1D rat neurones. An age‐related prolongation of both IK(Ca) decay and [Ca2+]i clearance was also seen after the removal of KA. It was thus concluded that the age‐related changes of ionotropic receptors appear to play a key role in the activities of immature and mature rat Meynert cholinergic neurones. The KA‐induced IK(Ca), which developed with ageing, may thus function as one of the negative feedback systems, and thereby prevent excess cell excitation and neural damage, especially in adult rats.

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Selective block of recombinant glur6 receptors by NS-102, a novel non-NMDA receptor antagonist

Cited by 117 publications

References 16 publications

Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release

Medicinal Chemistry of Competitive Kainate Receptor Antagonists

Age‐related functional changes of the glutamate receptor channels in rat Meynert neurones

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