A comprehensive description of GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonists

Liu, Wenwu; Jiang, Xiaowen; Zu, Yuxin; Yang, Yue; Liu, Yaqian; Sun, Xue; Xu, Zihua; Ding, Huaiwei; Zhao, Qingchun

doi:10.1016/j.ejmech.2020.112447

Cited by 51 publications

(40 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, GluN2B NAMs are better tolerated than most highaffinity and nonselective NMDA receptor channel blockers and competitive antagonists, and thus there is high therapeutic potential for this class of NAMs. For this reason, novel GluN2B-selective NAMs have been developed by both industry and academic groups, which resulted in many classes of GluN2Bselective NAMs with diverse scaffolds (Santangelo et al, 2012;Hashimoto et al, 2013;Lai et al, 2014;Shipton and Paulsen, 2013;Strong et al, 2014;Liu et al, 2020b). A number of structural analogs of ifenprodil with a shared piperidine core have been developed and exhibit improved potency and selectivity, including Ro 25-6981 (Fischer et al, 1997), CP- l Shows some activity at GluA2 recombinant AMPA receptors.…”

Section: B Nmda Receptor Modulatorsmentioning

confidence: 99%

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Hansen¹,

Wollmuth²,

Bowie³

et al. 2021

Pharmacol Rev

328

445

View full text Add to dashboard Cite

Section: B Nmda Receptor Modulatorsmentioning

confidence: 99%

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Hansen¹,

Wollmuth²,

Bowie³

et al. 2021

Pharmacol Rev

328

445

View full text Add to dashboard Cite

“…There are three main classes of iGluRs which are structurally and pharmacologically different: NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate (KA) receptors. 5,6 NMDA receptors are important for initiating long-term neuronal plasticity such as long-term potentiation, 7,8 whereas AMPA receptors control fast excitatory synaptic transmission and plasticity. 9,10 Both of these receptors were found to be associated with pain development, and both NMDA and AMPA receptor antagonists were aid in the treatment of pain.…”

Section: Introductionmentioning

confidence: 99%

The emerging role of kainate receptor functional dysregulation in pain

Guan

et al. 2021

Mol Pain

View full text Add to dashboard Cite

Pain is a serious clinical challenge, and is associated with a significant reduction in quality of life and high financial costs for affected patients. Research efforts have been made to explore the etiological basis of pain to guide the future treatment of patients suffering from pain conditions. Findings from studies using KA (kainate) receptor agonist, antagonists and receptor knockout mice suggested that KA receptor dysregulation and dysfunction may govern both peripheral and central sensitization in the context of pain. Additional evidence showed that KA receptor dysfunction may disrupt the finely-tuned process of glutamic acid transmission, thereby contributing to the onset of a range of pathological contexts. In the present review, we summarized major findings in recent studies which examined the roles of KA receptor dysregulation in nociceptive transmission and in pain. This timely overview of current knowledge will help to provide a framework for future developing novel therapeutic strategies to manage pain.

show abstract

“…The NR2B subunit is involved in neurodegenerative processes in patients with Parkinson’s and Huntington’s diseases as well as AD [ 33 ]. Therefore, efficient modulators of GluN2B-containing NMDARs are a promising tool for further investigation and potential treatment of these diseases [ 34 , 35 , 36 ].…”

Section: Resultsmentioning

confidence: 99%

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

et al. 2021

View full text Add to dashboard Cite

A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.

show abstract

A comprehensive description of GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonists

Cited by 51 publications

References 155 publications

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

The emerging role of kainate receptor functional dysregulation in pain

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

Contact Info

Product

Resources

About