NR2B Selective NMDA Receptor Antagonists

Nikam, Sham S.; Meltzer, Leonard T.

doi:10.2174/1381612024607072

Cited by 91 publications

(55 citation statements)

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“…Memantine demonstrates that clinical success can be achieved with NMDA antagonists of unique pharmacological characteristics. Another class of compounds that has gained attention as having such potential is the GluN2B subunit-selective NMDA receptor antagonists (Chazot, 2004;Gogas, 2006;Mony et al, 2009), for which a rich pharmacology exists (Chenard and Menniti, 1999;Nikam and Meltzer, 2002;McCauley, 2005;Layton et al, 2006). By blocking only one NMDA receptor subtype, these compounds could have therapeutic benefits but minimize on-target side effects.…”

Section: The Next Generation N-methyl-d-aspartate Receptor Antagonmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Section: The Next Generation N-methyl-d-aspartate Receptor Antagonmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…The broad SAR governing these compound classes has typically involved two aromatic rings separated by a carbon linker that often contains nitrogen (Chenard and Menniti, 1999;Tamiz et al, 1999;Nikam and Meltzer, 2002;Borza and Domá ny, 2006;Layton et al, 2006). A variety of chemically distinct linkers and substituted aryl compounds retain activity, leading to considerable diversity in ligand structure.…”

Section: The Glun2b Amino-terminal Domain Harbors a Binding Site For mentioning

confidence: 99%

Control of Assembly and Function of Glutamate Receptors by the Amino-Terminal Domain

Hansen¹,

Furukawa²,

Traynelis³

2010

Mol Pharmacol

103

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The extracellular amino-terminal domains (ATDs) of the ionotropic glutamate receptor subunits form a semiautonomous component of all glutamate receptors that resides distal to the membrane and controls a surprisingly diverse set of receptor functions. These functions include subunit assembly, receptor trafficking, channel gating, agonist potency, and allosteric modulation. The many divergent features of the different ionotropic glutamate receptor classes and different subunits within a class may stem from differential regulation by the amino-terminal domains. The emerging knowledge of the structure and function of the amino-terminal domains reviewed here may enable targeting of this region for the therapeutic modulation of glutamatergic signaling. Toward this end, NMDA receptor antagonists that interact with the GluN2B ATD show promise in animal models of ischemia, neuropathic pain, and Parkinson's disease.

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“…The NR2B subunit selective antagonists showed potency in animal models of neurodegeneration [99], Parkinson disease [155,156,200,220], and hyperalgesia [19,29,36,57]. It was also realized that this type of compounds lacks the serious side effects of the classic NMDAR antagonists' [162]. Although, like other un-competitive NMDAR antagonists they may have some adverse effect on learning and memory, it was proved that they have a wider separation between doses that are effective in seizure or stroke models and those that disrupt learning and memory.…”

Section: Nr2b Subunit Selective Nmdar Antagonistsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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NR2B Selective NMDA Receptor Antagonists

Cited by 91 publications

References 0 publications

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Control of Assembly and Function of Glutamate Receptors by the Amino-Terminal Domain

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

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