Discovery of novel brain-penetrant GluN2B NMDAR antagonists via pharmacophore-merging strategy as anti-stroke therapeutic agents

Xu, Qinlong; Hu, Mengqi; Li, Jiaming; Ma, Xiaodong; Chu, Zhaoxing; Zhu, Qihua; Zhang, Yanchun; Zhu, Panhu; Huang, Yuanzheng; He, Guangwei

doi:10.1016/j.ejmech.2021.113876

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…68 Xu and colleagues synthesized a series of novel selective-GluN2B antagonists via hybridizing ifenprodil with RS-3-Nbutylphthalide (RS-NBP) to treat IS. 69 The resulted 8 (Figure 2) exhibited neuroprotective activity, superior to Nerinetide (9, NA-1, TAT-NR2B9c, Figure 2) consists of 20 amino acid residues (H-YGRKKRRQRRR-KLSSIESDV-OH), including the last nine C-terminal residues of GluN2B fused to the cationic cell-penetrating peptide TAT. This interfering peptide permeated cell membranes and efficiently disrupted the intracellular interaction of NMDAR with PSD-95, inhibiting NR2A and NR2B binding to PSD-95 with IC 50 values of 0.5 and 8 μM, respectively.…”

Section: Nmdars Antagonistsmentioning

confidence: 99%

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Jia,

Jiao,

Wang

et al. 2023

Medicinal Research Reviews

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Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long‐term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti‐IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti‐IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti‐IS drugs/agents are briefly provided to move the field forward.

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Section: Nmdars Antagonistsmentioning

confidence: 99%

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Jia,

Jiao,

Wang

et al. 2023

Medicinal Research Reviews

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“…C. E. Fischer discovered by in silico screening exhibited competitive activity against the binding of [ 3 H]ifenprodil to the NMDA-GluN2B receptor with a K i value in the submicromolar range ( K i = 113.87 ± 10.65 nM) . In addition, it displayed a neuroprotective effect against NMDA-induced neurotoxicity in rat hippocampal neurons, thereby offering a potential template for extensive structural optimization for attaining NMDA-GluN2B receptor antagonists . As revealed by the molecular docking of Pierardine to the NMDA-GluN2B receptor (PDB entry 5EWJ), it was engaged in H-bond interaction with Gln-110 (Figure A), and the phthalide template occupied a hydrophobic pocket surrounded by Pro-177, Thr-233, Glu-106, and Phe-176 (Figure B).…”

Section: Design Of Nmdar-glun2b Antagonistsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment

Lin,

Xu,

et al. 2024

J. Med. Chem.

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A series of structurally novel GluN2B NMDAR antagonists were designed, synthesized, and biologically evaluated as anti-stroke therapeutics by optimizing the chemical structure of Pierardine, the active ingredient of traditional Chinese medicine Dendrobium aphyllum (Roxb.) C. E. Fischer identified via in silico screening. The systematic structure−activity relationship study led to the discovery of 58 with promising NMDAR-GluN2B binding affinity and antagonistic activity. Of the two enantiomers, S-58 exhibited significant inhibition (IC 50 = 74.01 ± 12.03 nM) against a GluN1/GluN2B receptor-mediated current in a patch clamp assay. In addition, it displayed favorable specificity over other subtypes and off-target receptors. In vivo, S-58 exerted therapeutic efficacy comparable to that of the approved GluN2B NMDAR antagonist ifenprodil and excellent safety profiles. In addition to the attractive in vitro and in vivo potency, S-58 exhibited excellent brain exposure. In light of these merits, S-58 has been advanced to further preclinical investigation as a potential anti-stroke candidate.

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“…Along with progress in the reduction of adverse effects, the pH-dependent GluN2BR-selective antagonists, the 93-series, may be more clinically promising because they have less impact on the healthy brain at normal pH [ 49 ]. A novel synthesized brain-penetrant GluN2BR antagonist called compound 45e also exhibits superior neuroprotective activity [ 50 ]. By contrast, some current studies prefer to exploit GluN2AR-positive allosteric modulators to enhance neuronal survival signaling [ 51 , 52 ].…”

Section: Excitotoxicity and Neuronal Deathmentioning

confidence: 99%

Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke

et al. 2022

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Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability, which gravely burdens the global economy. Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy. Even so, patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury. It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies. Regarding the pathogenesis, multiple pathological events trigger the activation of cell death pathways. Particular attention should be devoted to excitotoxicity, oxidative stress, and inflammatory responses. Thus, in this article, we first review the principal mechanisms underlying neuronal death mediated by these significant events, such as intrinsic and extrinsic apoptosis, ferroptosis, parthanatos, pyroptosis, necroptosis, and autophagic cell death. Then, we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.

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Discovery of novel brain-penetrant GluN2B NMDAR antagonists via pharmacophore-merging strategy as anti-stroke therapeutic agents

Cited by 9 publications

References 34 publications

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment

Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke

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