New advances in NMDA receptor pharmacology

Ogden, Kevin K.; Traynelis, Stephen F.

doi:10.1016/j.tips.2011.08.003

Cited by 180 publications

(175 citation statements)

References 71 publications

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“…NMDARs non-selectively, whereas the GluN2A subunit is antagonized by the competitive antagonist NVP-AAM077, which was further demonstrated to have a better selectivity for the GluN2D subunit; the GluN2B subunit is also selectively blocked by the non-competitive antagonists ifenprodil and Ro 25-6981, among others (reviewed by Ogden and Traynelis, 2011). Recently, TCN201 was described as a potent GluN2A…”

Section: + and Mk-801 Are Channel Blockers And D-apv Is A Competitivmentioning

confidence: 99%

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota¹,

Ferreira²,

Rego³

2014

Neuropharmacology

173

100

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Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly.Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre-and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.

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Section: + and Mk-801 Are Channel Blockers And D-apv Is A Competitivmentioning

confidence: 99%

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota¹,

Ferreira²,

Rego³

2014

Neuropharmacology

173

100

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“…The GluN2 subunits therefore determine the physiological roles of NMDA receptor subtypes, and, for this reason, they have received considerable interest as potential therapeutic targets. To this end, ligands that distinguish NMDA receptor subtypes based on GluN2 subunits are desirable due to their obvious utility as pharmacological tools and as potential therapeutic agents for the treatment of CNS disorders (7,8).…”

mentioning

confidence: 99%

“…Considerable progress has been made in the development of subunit-selective allosteric modulators (7)(8)(9)(10)(11)(12)(13), but the development of subtype-selective competitive NMDA receptor antagonists has been less successful. The competitive glutamate-site antagonist NVP-AAM077 (hereafter NVP) was originally reported to have 100-fold preference for GluN1/2A over GluN1/2B (14).…”

mentioning

confidence: 99%

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Lind

Mou

Tamborini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

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“…HAD contributes to functional deficits such as learning and memory decline, cognitive and reasoning dysfunction, inattention, impaired motor skills, and abulia, among others (Singer et al, 2010;Rosca et al, 2012;Peluso and Spudich 2014). More importantly, gp120 can activate macrophages resulting in the production of copious amounts of chemokines/cytokines, and can also influence glutamate uptake in astrocytes and interfere with the glutamine supply for neurons, severely impacting learning and memory (Hazleton et al, 2010;Ogden and Traynelis 2011;Fields et al, 2014). Through behavioral testing in the first week, we found that the average escape latency and number of errors in gp120-treated groups were higher than those of Ctrl rats, indicating that gp120 affected learning and memory in rats.…”

Section: Discussionmentioning

confidence: 99%

P2X<sub>7</sub> receptor in the hippocampus is involved in gp120-induced cognitive dysfunction

et al. 2017

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ABSTRACT.To investigate the role of the P2X 7 receptor in learning and memory dysfunction induced by HIV-1 envelope glycoprotein gp120 (gp120), we established HIV-1-associated dementia (HAD) animal models by intracerebroventricular (ICV) infusion of gp120 in rats. We observed gp120-induced cognitive dysfunction in the radial arm water maze test. Results showed that rats in the gp120 groups had longer escape latencies and more errors compared to those in the control group. For example, the average trial time in the 50-ng/daygp120 group on day eight (16.57 ± 1.71 s, N = 90) was significantly longer than that of control rats (9.93 ± 0.68 s, N = 90). The relative expression of P2X 7 mRNA in the control, 50-, 70-, and 100-ng/daygp120 groups were 0.43 ± 0.06, 0.48 ± 0.07, 0.83 ± 0.05, and 0.84 ± 0.10, respectively; relative P2X 7 protein expression in those groups was 0.63 ± 0.07, 1.08 ± 0.06, 0.90 ± 0.07, and 1.03 ± 0.11, respectively. According to immunohistochemistry analysis, the staining intensity values for P2X 7 protein expression in the control, 50-, 70-, and 100-ng/ d-gp120 groups were 0.88 ± 0.07, 1.41 ± 0.12, 1.28 ± 0.13, and 1.31 ± 0.10, respectively. The above results showed that the expression of P2X 7 increased significantly in the hippocampus of gp120 rats compared to that of the control group. These results suggest that ICV infusion of gp120 can successfully mimic HAD in rats, and P2X 7 may be involved in gp120-induced cognitive dysfunction. This could provide a theoretical foundation and potential drug target for research and treatment of ADC.

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New advances in NMDA receptor pharmacology

Cited by 180 publications

References 71 publications

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

P2X<sub>7</sub> receptor in the hippocampus is involved in gp120-induced cognitive dysfunction

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