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Pharmacological Insight into NMDA Receptor Antagonists
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Pharmacological Insight into NMDA Receptor Antagonists

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

Deadline for manuscript submissions: 25 November 2024 | Viewed by 7917

Special Issue Editor

Dr. Franck Jean Talmont

E-Mail Website
Guest Editor
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31059 Toulouse, France
Interests: NMDA receptor; G-protein-coupled receptors; opioid receptors; antidepressants; neurological disorders; multiple sclerosis

Special Issue Information

Dear Colleagues,

The N-methyl-D-aspartate (NMDA) receptor belongs to the glutamate sensing receptor family. This ionotropic hetero-tetrameric receptor displays an essential neuronal function and is deeply implicated in memory and learning processes, and is more consistently associated with synaptic plasticity in the central nervous system. The activation of NMDA receptors follows the binding of two co-agonists amino acids, glutamate and glycine, as well as the removal of blocking Mg2+ ions from the inner channel via membrane depolarization and Ca++ entry in neuron dendrites. Besides the physiological role of NMDA receptors, this receptor is also known for inferring the hallucinogenic effects of recreational drugs (such as ketamine, PCP, or dextromethorphan). Research on new drug candidates acting as noncompetitive NMDA antagonists has had renewed interest since ketamine (esketamine) has been repurposed as an antidepressant. The search for new radiotracers that can discriminate the open state of the NMDA receptor in the context of neurodegenerative diseases is also of major importance.

In this Special Issue, we aim to draw together research from experts in a field that highlights new drugs and radiotracers that act as noncompetitive NMDA antagonists.

I look forward to your valuable contribution.

Dr. Franck Jean Talmont
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

  • ionotropic receptors
  • NMDA receptors
  • antidepressants
  • radiotracers
  • neurodegenerative diseases

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Published Papers (4 papers)

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Research

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16 pages, 6557 KiB  
Article
Mechanisms of NMDA Receptor Inhibition by Biguanide Compounds
by Arseniy S. Zhigulin, Anastasiya O. Novikova and Oleg I. Barygin
Pharmaceuticals 2024, 17(9), 1234; https://doi.org/10.3390/ph17091234 - 19 Sep 2024
Viewed by 721
Abstract
N-methyl-D-aspartate (NMDA) receptors are inhibited by many medicinal drugs. The recent successful repurposing of NMDA receptor antagonists ketamine and dextromethorphan for the treatment of major depressive disorder further enhanced the interest in this field. In this work, we performed a screening for the [...] Read more.
N-methyl-D-aspartate (NMDA) receptors are inhibited by many medicinal drugs. The recent successful repurposing of NMDA receptor antagonists ketamine and dextromethorphan for the treatment of major depressive disorder further enhanced the interest in this field. In this work, we performed a screening for the activity against native NMDA receptors of rat CA1 hippocampal pyramidal neurons among biguanide compounds using the whole-cell patch-clamp method. Antimalarial biguanides proguanil and cycloguanil, as well as hypoglycemic biguanide phenformin, inhibited them in micromolar concentrations, while another hypoglycemic biguanide metformin and antiviral biguanide moroxydine were practically ineffective. IC50 values at −80 mV holding voltage were 3.4 ± 0.6 µM for cycloguanil, 9.0 ± 2.2 µM for proguanil and 13 ± 1 µM for phenformin. The inhibition by all three compounds was not competitive. Cycloguanil acted as an NMDA receptor voltage-dependent trapping channel blocker, while proguanil and phenformin acted as allosteric inhibitors. Our results support the potential clinical repurposing of biguanide compounds for the treatment of neurodegenerative disorders linked to glutamatergic excitotoxicity while also providing a better understanding of structural determinants of NMDA receptor antagonism by biguanides. Full article
(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)
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19 pages, 2031 KiB  
Article
Use of Quantitative Electroencephalography to Inform Age- and Sex-Related Differences in NMDA Receptor Function Following MK-801 Administration
by Kimberly M. Holter, Alex D. Lekander, Bethany E. Pierce, L. Paul Sands and Robert W. Gould
Pharmaceuticals 2024, 17(2), 237; https://doi.org/10.3390/ph17020237 - 11 Feb 2024
Viewed by 1548
Abstract
Sex- and age-related differences in symptom prevalence and severity have been widely reported in patients with schizophrenia, yet the underlying mechanisms contributing to these differences are not well understood. N-methyl-D-aspartate (NMDA) receptor hypofunction contributes to schizophrenia pathology, and preclinical models often use [...] Read more.
Sex- and age-related differences in symptom prevalence and severity have been widely reported in patients with schizophrenia, yet the underlying mechanisms contributing to these differences are not well understood. N-methyl-D-aspartate (NMDA) receptor hypofunction contributes to schizophrenia pathology, and preclinical models often use NMDA receptor antagonists, including MK-801, to model all symptom clusters. Quantitative electroencephalography (qEEG) represents a translational approach to measure neuronal activity, identify targetable biomarkers in neuropsychiatric disorders and evaluate possible treatments. Abnormalities in gamma power have been reported in patients with schizophrenia and correspond to psychosis and cognitive impairment. Further, as gamma power reflects cortical glutamate and GABA signaling, it is highly sensitive to changes in NMDA receptor function, and NMDA receptor antagonists aberrantly increase gamma power in rodents and humans. To evaluate the role of sex and age on NMDA receptor function, MK-801 (0.03–0.3 mg/kg, SC) was administered to 3- and 9-month-old male and female Sprague–Dawley rats that were implanted with wireless EEG transmitters to measure cortical brain function. MK-801-induced elevations in gamma power were observed in 3-month-old male and female and 9-month-old male rats. In contrast, 9-month-old female rats demonstrated blunted maximal elevations across a wide dose range. Importantly, MK-801-induced hyperlocomotor effects, a common behavioral screen used to examine antipsychotic-like activity, were similar across all groups. Overall, sex-by-age-related differences in gamma power support using qEEG as a translational tool to evaluate pathological progression and predict treatment response across a heterogeneous population. Full article
(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)
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Review

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25 pages, 1720 KiB  
Review
NMDA Receptors: Distribution, Role, and Insights into Neuropsychiatric Disorders
by Marie Beaurain, Anne-Sophie Salabert, Pierre Payoux, Emmanuel Gras and Franck Talmont
Pharmaceuticals 2024, 17(10), 1265; https://doi.org/10.3390/ph17101265 - 25 Sep 2024
Viewed by 1908
Abstract
Background: N-methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family. These ligand-gated channels are entwined with numerous fundamental neurological functions within the central nervous system (CNS), and numerous neuropsychiatric disorders may arise from their malfunction. Methods: The purpose of the present [...] Read more.
Background: N-methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family. These ligand-gated channels are entwined with numerous fundamental neurological functions within the central nervous system (CNS), and numerous neuropsychiatric disorders may arise from their malfunction. Methods: The purpose of the present review is to provide a detailed description of NMDARs by addressing their molecular structures, activation mechanisms, and physiological roles in the mammalian brain. In the second part, their role in various neuropsychiatric disorders including stroke, epilepsy, anti-NMDA encephalitis, Alzheimer’s and Huntington’s diseases, schizophrenia, depression, neuropathic pain, opioid-induced tolerance, and hyperalgesia will be covered. Results: Finally, through a careful exploration of the main non-competitive NMDARs antagonists (channel-blockers). Conclusion: We discuss the strengths and limitations of the various molecular structures developed for diagnostic or therapeutic purposes. Full article
(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)
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25 pages, 4315 KiB  
Review
NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders
by Ayodeji Olatunde Egunlusi and Jacques Joubert
Pharmaceuticals 2024, 17(5), 639; https://doi.org/10.3390/ph17050639 - 15 May 2024
Cited by 4 | Viewed by 2740
Abstract
Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). The global prevalence of NDs is on the rise, imposing significant economic [...] Read more.
Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). The global prevalence of NDs is on the rise, imposing significant economic and social burdens. Despite extensive research, the mechanisms underlying NDs remain incompletely understood, hampering the development of effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, is a key pathological process implicated in NDs. Targeting the N-methyl-D-aspartate (NMDA) receptor, which plays a central role in excitotoxicity, holds therapeutic promise. However, challenges, such as blood–brain barrier penetration and adverse effects, such as extrapyramidal effects, have hindered the success of many NMDA receptor antagonists in clinical trials. This review explores the molecular mechanisms of NMDA receptor antagonists, emphasizing their structure, function, types, challenges, and future prospects in treating NDs. Despite extensive research on competitive and noncompetitive NMDA receptor antagonists, the quest for effective treatments still faces significant hurdles. This is partly because the same NMDA receptor that necessitates blockage under pathological conditions is also responsible for the normal physiological function of NMDA receptors. Allosteric modulation of NMDA receptors presents a potential alternative, with the GluN2B subunit emerging as a particularly attractive target due to its enrichment in presynaptic and extrasynaptic NMDA receptors, which are major contributors to excitotoxic-induced neuronal cell death. Despite their low side-effect profiles, selective GluN2B antagonists like ifenprodil and radiprodil have encountered obstacles such as poor bioavailability in clinical trials. Moreover, the selectivity of these antagonists is often relative, as they have been shown to bind to other GluN2 subunits, albeit minimally. Recent advancements in developing phenanthroic and naphthoic acid derivatives offer promise for enhanced GluN2B, GluN2A or GluN2C/GluN2D selectivity and improved pharmacodynamic properties. Additional challenges in NMDA receptor antagonist development include conflicting preclinical and clinical results, as well as the complexity of neurodegenerative disorders and poorly defined NMDA receptor subtypes. Although multifunctional agents targeting multiple degenerative processes are also being explored, clinical data are limited. Designing and developing selective GluN2B antagonists/modulators with polycyclic moieties and multitarget properties would be significant in addressing neurodegenerative disorders. However, advancements in understanding NMDA receptor structure and function, coupled with collaborative efforts in drug design, are imperative for realizing the therapeutic potential of these NMDA receptor antagonists/modulators. Full article
(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)
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