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Pharmaceuticals
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NMDA Receptor-Based Therapeutics
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NMDA Receptor-Based Therapeutics

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 19457

Special Issue Editor

Dr. Antonius M. J. VanDongen

E-Mail Website
Guest Editor
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708, USA
Interests: NMDA receptor; drug design; Alzheimer’s disease; epigenetics; memory

Special Issue Information

Dear Colleagues,

The NMDA receptor is a member of the ionotropic glutamate receptor family which plays a critical role in both brain development and memory processes. Physiological activation of the NMDA receptor is required for setting up the correct neuronal wiring of the developing brain and for initiating alterations in synaptic strength that are required for the formation and maintenance of memories. However, both over-activation and hypofunction of the NMDA receptor can have deleterious effects on higher-order brain function. Because it plays such a critical role in multiple processes underlying cognitive functions, NMDA receptor dysfunction has been implicated in the pathophysiology of several disorders of the central nervous system, including encephalitis, stroke, epilepsy, schizophrenia, autism, intellectual disability, depression and mood disturbances, and neurodegenerative disease. This Special Issue of Pharamaceutics will focus on the development of NMDA-receptor-based therapeutics for treating these disorders, as well as the progress made in understanding the underlying mechanisms.

Dr. Antonius M. J. VanDongen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NMDA receptor
  • therapeutics
  • drugs
  • stroke
  • Alzheimer’s disease
  • schizophrenia
  • depression
  • epilepsy
  • encephalitis

Published Papers (7 papers)

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Research

Jump to: Review

12 pages, 1207 KiB  
Article
NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder
by Yu-Chin Hsiao, Mei-Yi Lee, Ming-Huan Chan and Hwei-Hsien Chen
Pharmaceuticals 2023, 16(6), 812; https://doi.org/10.3390/ph16060812 - 30 May 2023
Viewed by 1368
Abstract
Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of [...] Read more.
Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague–Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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22 pages, 2869 KiB  
Article
Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors
by Ezio Bettini, Stephen M. Stahl, Sara De Martin, Andrea Mattarei, Jacopo Sgrignani, Corrado Carignani, Selena Nola, Patrizia Locatelli, Marco Pappagallo, Charles E. Inturrisi, Francesco Bifari, Andrea Cavalli, Andrea Alimonti, Luca Pani, Maurizio Fava, Sergio Traversa, Franco Folli and Paolo L. Manfredi
Pharmaceuticals 2022, 15(8), 997; https://doi.org/10.3390/ph15080997 - 13 Aug 2022
Cited by 10 | Viewed by 2830
Abstract
Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers [...] Read more.
Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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17 pages, 2903 KiB  
Article
The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin
by Ezio Bettini, Sara De Martin, Andrea Mattarei, Marco Pappagallo, Stephen M. Stahl, Francesco Bifari, Charles E. Inturrisi, Franco Folli, Sergio Traversa and Paolo L. Manfredi
Pharmaceuticals 2022, 15(7), 882; https://doi.org/10.3390/ph15070882 - 17 Jul 2022
Cited by 6 | Viewed by 2688
Abstract
REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca2+] [...] Read more.
REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca2+]in) in recombinant cell lines expressing human GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, and GluN1-GluN2D NMDAR subtypes. There were no effects of QA on [Ca2+]in in cells expressing GluN1-GluN2C subtypes. QA acted as a low-potency, subtype-selective, NMDAR partial agonist in GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D subtypes. REL-1017 reduced [Ca2+]in induced by QA. In cells expressing the GluN1-GluN2D subtype, QA acted as an agonist in the presence of 0.04 μM L-glutamate and as an antagonist in the presence of 0.2 μM L-glutamate. REL-1017 reduced [Ca2+]in induced by L-glutamate alone and with QA in all cell lines. In the absence of L-glutamate, gentamicin had no effect. Gentamicin was a positive modulator for GluN1-GluN2B subtypes at 10 μM L-glutamate, for GluN1-GluN2A at 0.2 μM L-glutamate, and for GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D at 0.04 μM L-glutamate. No significant changes were observed with GluN1-GluN2C NMDARs. REL-1017 reduced [Ca2+]in induced by the addition of L-glutamate in all NMDAR cell lines in the presence or absence of gentamicin. In conclusion, REL-1017 reduced [Ca2+]in induced by L-glutamate alone and when increased by QA and gentamicin. REL-1017 may protect cells from excessive calcium entry via NMDARs hyperactivated by endogenous and exogenous molecules. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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12 pages, 2250 KiB  
Article
Virtual Therapy with the NMDA Antagonist Memantine in Hippocampal Models of Moderate to Severe Alzheimer’s Disease, in Silico Trials
by Dariusz Świetlik, Jacek Białowąs, Aida Kusiak and Marta Krasny
Pharmaceuticals 2022, 15(5), 546; https://doi.org/10.3390/ph15050546 - 28 Apr 2022
Cited by 8 | Viewed by 1660
Abstract
The variability in clinical trial results on memantine treatment of Alzheimer’s disease remains incompletely explained. The aim of this in silico study is a virtual memantine therapy for Alzheimer’s disease that provides a different perspective on clinical trials; An in silico randomised trial [...] Read more.
The variability in clinical trial results on memantine treatment of Alzheimer’s disease remains incompletely explained. The aim of this in silico study is a virtual memantine therapy for Alzheimer’s disease that provides a different perspective on clinical trials; An in silico randomised trial using virtual hippocampi to treat moderate to severe Alzheimer’s disease with doses of memantine 3–30 µM compared to placebo. The primary endpoint was the number of impulses (spikes). Secondary endpoints included interspike interval and frequency; The number of virtual moderate-AD hippocampal spikes was significantly lower, at 1648.7 (95% CI, 1344.5–1952.9), versus those treated with the 3 µM dose, 2324.7 (95% CI, 2045.9–2603.5), and the 10 µM dose, 3607.0 (95% CI, 3137.6–4076.4). In contrast, the number of virtual spikes (spikes) of severe AD of the hippocampus was significantly lower, at 1461.8 (95% CI, 1196.2–1727.4), versus those treated with the 10 µM dose, at 2734.5 (95% CI, 2369.8–3099.2), and the 30 µM dose, at 3748.9 (95% CI, 3219.8–4278.0). The results of the analysis of secondary endpoints, interspike intervals and frequencies changed statistically significantly relative to the placebo; The results of the in silico study confirm that memantine monotherapy is effective in the treatment of moderate to severe Alzheimer’s disease, as assessed by various neuronal parameters. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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Review

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15 pages, 1708 KiB  
Review
The Disruption of NMDAR/TRPM4 Death Signaling with TwinF Interface Inhibitors: A New Pharmacological Principle for Neuroprotection
by Jing Yan and Hilmar Bading
Pharmaceuticals 2023, 16(8), 1085; https://doi.org/10.3390/ph16081085 - 31 Jul 2023
Cited by 3 | Viewed by 1240
Abstract
With the discovery that the acquisition of toxic features by extrasynaptic NMDA receptors (NMDARs) involves their physical interaction with the non-selective cation channel, TRPM4, it has become possible to develop a new pharmacological principle for neuroprotection, namely the disruption of the NMDAR/TRPM4 death [...] Read more.
With the discovery that the acquisition of toxic features by extrasynaptic NMDA receptors (NMDARs) involves their physical interaction with the non-selective cation channel, TRPM4, it has become possible to develop a new pharmacological principle for neuroprotection, namely the disruption of the NMDAR/TRPM4 death signaling complex. This can be accomplished through the expression of the TwinF domain, a 57-amino-acid-long stretch of TRPM4 that mediates its interaction with NMDARs, but also using small molecule TwinF interface (TI) inhibitors, also known as NMDAR/TRPM4 interaction interface inhibitors. Both TwinF and small molecule TI inhibitors detoxify extrasynaptic NMDARs without interfering with synaptic NMDARs, which serve important physiological functions in the brain. As the toxic signaling of extrasynaptic NMDARs contributes to a wide range of neurodegenerative conditions, TI inhibitors may offer therapeutic options for currently untreatable human neurodegenerative diseases including Amyotrophic Lateral Sclerosis, Alzheimer’s disease, and Huntington’s disease. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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30 pages, 1391 KiB  
Review
The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders
by Kevin Lee, Zoe Mills, Pangying Cheung, Juliette E. Cheyne and Johanna M. Montgomery
Pharmaceuticals 2023, 16(1), 1; https://doi.org/10.3390/ph16010001 - 20 Dec 2022
Cited by 4 | Viewed by 4406
Abstract
NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly [...] Read more.
NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly modulated by zinc, which is co-released with glutamate and concentrates in postsynaptic spines. Both NMDARs and zinc have been strongly linked to autism spectrum disorders (ASDs), suggesting that NMDARs are an important player in the beneficial effects observed with zinc in both animal models and children with ASDs. Significant evidence is emerging that these beneficial effects occur via zinc-dependent regulation of SHANK proteins, which form the backbone of the postsynaptic density. For example, dietary zinc supplementation enhances SHANK2 or SHANK3 synaptic recruitment and rescues NMDAR deficits and hypofunction in Shank3ex13–16−/− and Tbr1+/− ASD mice. Across multiple studies, synaptic changes occur in parallel with a reversal of ASD-associated behaviours, highlighting the zinc-dependent regulation of NMDARs and glutamatergic synapses as therapeutic targets for severe forms of ASDs, either pre- or postnatally. The data from rodent models set a strong foundation for future translational studies in human cells and people affected by ASDs. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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20 pages, 722 KiB  
Review
Targeting NMDA Receptor Complex in Management of Epilepsy
by Shravan Sivakumar, Mehdi Ghasemi and Steven C. Schachter
Pharmaceuticals 2022, 15(10), 1297; https://doi.org/10.3390/ph15101297 - 21 Oct 2022
Cited by 7 | Viewed by 4091
Abstract
N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology [...] Read more.
N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology of seizure disorders and epilepsy. Accordingly, NMDAR modulators have been shown to exert anticonvulsive effects in various preclinical models of seizures, as well as in patients with epilepsy. In this review, we provide an update on the pathologic role of NMDARs in epilepsy and an overview of the NMDAR antagonists that have been evaluated as anticonvulsive agents in clinical studies, as well as in preclinical seizure models. Full article
(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)
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