NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders
Abstract
:1. Introduction
2. Structure and Functions of NMDA Receptors
3. Types and Molecular Mechanisms of NMDA Receptor Antagonists
3.1. Competitive NMDA Receptor Antagonist
3.2. Uncompetitive or Non-Competitive NMDA Receptor Antagonists
3.3. Allosteric NMDA Receptor Antagonists
Antagonist Type | Compounds | Receptor Subunits/Subtypes | Developmental Stage | Pharmacological Profiles | Side-Effect Profiles | References |
---|---|---|---|---|---|---|
Competitive antagonists | D-CPP/D-CPP-ene (Midafotel) | GluN2A | Terminated at Phase 11 clinical trials | Antiepileptic and neuroprotective effects against head injury, cerebral ischemia and stroke Alteration of acute behavioural response to cocaine. Stimulate short-term increase in NREM (non-rapid eye movement) sleep | Hallucinations Poor concentration Confusion Gait ataxia Sedation Depression | [28,39,42,54,55,68,107] |
D-AP5/D-AP7 | Non-subunit selective | Preclinical or experimental studies | Block fear acquisition and expression Block or interfere with acute response to psychostimulants such as cocaine amphetamine, or methamphetamine | Similar to those of D-CPP-ene/D-CPP | [28,55] | |
DCKA | GluN1 | Preclinical or experimental studies | Anxiolytic effect Neuroprotective against NMDA/glycine-induced toxicity | Lack of psychotomimetic effects or side effects associated with dopaminergic transmission | [28,56,108,109,110] | |
CGP-78608, CGP-37849 & CGP-40116 | GluN1 | Preclinical or Experimental studies | Anticonvulsant effect | Lack of side effects associated with dopaminergic transmission | [28,45,64,68,111] | |
CGS-19755 (Selfotel) | GluN2A | Terminated at Phase III clinical trials | Neuroprotective effect against global and focal ischemia, trauma and stroke | Psychotomimetic side effects like Hallucination Confusion Paranoia Delirium Lack of side effects associated with dopaminergic transmission | [28,44,46,52,53] | |
L689-560 & L701-324 | GluN1 | Preclinical or experimental studies | Anticonvulsant effects Anxiolytic Antidepressant-like effect in mice | Sedation Lack of neuronal vacuolisation and psychotomimetic potential Ataxia at a high dose Modest impairment of reference memory, but no negative effect on working memory | [28,49,56,112,113,114,115,116] | |
PPDA | GluN2A, GluN2C &GluN2D | Preclinical or experimental studies | Prevent the complete worsening effect of tissue-type plasminogen activator on NMDA-induced neuronal death in both cultured cortical and hippocampal neurons Anti-allynic and anti-hyperalgesic effects in rat | Motor dysfunction at high dose | [28,41,58,60,117,118,119,120,121] | |
NVP-AAMO77 (PEAQX) | GluN2A GluN2C & GluN2B | Preclinical or experimental studies | Produce anti-compulsive behaviour in a rat model Impairment of contextual and temporal fear responses Antidepressant-like effect in rodents | Affect motor coordination stamina and motivation run in a rat dyskinesia model Motor memory impairment or learning memory deficit | [28,36,117,119,122,123,124,125,126] | |
SDZ-220-040 | GluN2B | Preclinical or experimental studies | Design to readily cross the BBB. Effectively disrupt prepulse inhibition in rats Anticonvulsant effect Protection against focal ischemia Attenuate neuropathic pain | Sedation Ataxia Psychotomimetic effects | [28,127,128,129] | |
Non-competitive antagonist | MK-801 | Open-Channel blocker | Preclinical or experimental studies | Reverse mild stress-induced anhedonia in male Wistar rats Neuroprotective effect in several animal models of cerebral ischaemia Block L-Dopa-induced dyskinesia in a rat preclinical model, but only at concentrations that worsen parkinsonism Anti-convulsant effect | Weight loss Hypothermia Death Hallucination Ataxia Hyperlocomotion | [53,61,63,66,130,131] |
Memantine | Open-channel blocker | Approved for AD in human | Neuroprotective effect in AD, vascular dementia and prodromal stages of psychosis Antidepressant-like effect Antinociceptive effect in rats Anticonvulsant effect | Occasional restlessness Headache Hypertension Drowsiness Constipation Diarrhoea Nausea Anorexia Dyspnea Slight dizziness at a high dose | [45,62,71,72,75,132,133,134] | |
Amantadine | Open-channel blocker | Approved for PD in human | Anti-dyskinetic effect Effectively reduce L-Dopa-induced abnormal involuntary movement Anti-convulsant effect Neuroprotective effect | Visual hallucination Confusion Blurred vision Leg oedema Dry mouth Constipation Urinary retention | [62,63,66,131,135] | |
PCP | Open-channel blocker | Preclinical/experimental studies | Anticonvulsant effects in NMDA- or quinolate-induced seizure model Anaesthetic effect | Hallucination Ataxia Hyperlocomotion Emergency delirium | [45,136] | |
Ketamine | Open-channel blocker | Approved as an anaesthetic agent | Anticonvulsant effect in NMDA- or quinolate-induced seizure model Anaesthetic effect Antidepressant effect in resistant major depressive disorder | Induce cognitive deficits and psychotic symptoms Hallucination Abuse Psychological and physiological dependences Possible neurotoxicity Nystagmus Drowsiness Nausea and vomiting Blood pressure elevation Liver and bladder damage | [45,130,132,133,136,137,138,139] | |
Tiletamine | Channel blocker | Approved for veterinary use | Anaesthetic effect Anticonvulsant effects in NMDA- or quinolate-induced seizure model | Robust Sedation in human and animal Ataxia Feeling of dissociation Hallucination | [136] | |
Negative allosteric modulator | Ifenprodil | GluN2B | Phase III clinical trials completed | Neuroprotective effect in both in vitro and in vivo models of cerebral ischemia Anticonvulsant effects in rodent Rapid antidepressant effect Alleviate neuropathic pain | Impair cognitive behavioural tasks | [28,81,85,93,100,134,140,141,142] |
Radiprodil | GluN2B | Terminated at Phase II clinical trials | Anticonvulsant effect in rate model (stronger in young rat pups than adult animals) Decrease epileptic spasms in infants | Vomiting Pyrexia | [100] | |
Ro25-6981 | GluN2B | Preclinical or experimental studies | Rapid antidepressant effect and counteract depressive-like behaviour in chronically stressed rodent Neuroprotective effect against glutamate-induced toxicity in a cultured cortical neuron Improve anxiety and compulsive behaviour in obsessive-compulsive disorder rat Alleviate cerebral ischemia-reperfusion and oxidative damage in male Sprague Dawley rats Antipakinsonian effect in 6-OHDA-lesioned and MPTP PD rat model | Reduced memory in early life stress mice | [28,88,143,144,145,146] | |
DQP-1105 | GluN2C & GluN2D | Preclinical or experimental studies | Neuroprotective effects in GluN2D-rich substantia nigra compacta dopaminergic neurons | Motor dysfunction | [28,103,147,148,149,150,151] |
4. Current Challenges and Future Perspectives
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wang, W.; Li, T.; Wang, Z.; Yin, Y.; Zhang, S.; Wang, C.; Hu, X.; Lu, S. Bibliometric Analysis of Research on Neurodegenerative Diseases and Single-Cell RNA Sequencing: Opportunities and Challenges. iScience 2023, 26, 107833. [Google Scholar] [CrossRef]
- Fratiglioni, L.; Qiu, C. Prevention of Common Neurodegenerative Disorders in the Elderly. Exp. Gerontol. 2009, 44, 46–50. [Google Scholar] [CrossRef]
- Ullah, M.F.; Ahmad, A.; Bhat, S.H.; Abu-Duhier, F.M.; Barreto, G.E.; Ashraf, G.M. Impact of Sex Differences and Gender Specificity on Behavioral Characteristics and Pathophysiology of Neurodegenerative Disorders. Neurosci. Biobehav. Rev. 2019, 102, 95–105. [Google Scholar] [CrossRef]
- Maselli, F.; D’Antona, S.; Utichi, M.; Arnaudi, M.; Castiglioni, I.; Porro, D.; Papaleo, E.; Gandellini, P.; Cava, C. Computational Analysis of Five Neurodegenerative Diseases Reveals Shared and Specific Genetic Loci. Comput. Struct. Biotechnol. J. 2023, 21, 5395–5407. [Google Scholar] [CrossRef]
- Joshi, R.; Missong, H.; Mishra, J.; Kaur, S.; Saini, S.; Kandimalla, R.; Reddy, P.H.; Babu, A.; Bhatti, G.K.; Bhatti, J.S. Nanotheranostics Revolutionizing Neurodegenerative Diseases: From Precision Diagnosis to Targeted Therapies. J. Drug Deliv. Sci. Technol. 2023, 89, 105067. [Google Scholar] [CrossRef]
- Arbo, B.D.; Schimith, L.E.; Goulart dos Santos, M.; Hort, M.A. Repositioning and Development of New Treatments for Neurodegenerative Diseases: Focus on Neuroinflammation. Eur. J. Pharmacol. 2022, 919, 174800. [Google Scholar] [CrossRef]
- Liu, W.; Li, Y.; Zhao, T.; Gong, M.; Wang, X.; Zhang, Y.; Xu, L.; Li, W.; Li, Y.; Jia, J. The Role of N-Methyl-D-Aspartate Glutamate Receptors in Alzheimer’s Disease: From Pathophysiology to Therapeutic Approaches. Prog. Neurobiol. 2023, 231, 102534. [Google Scholar] [CrossRef]
- Agid, Y. Neurodegenerative Disorders: Are We Wrong? Rev. Neurol. 2022, 178, 407–413. [Google Scholar] [CrossRef]
- Mendes, D.; Peixoto, F.; Oliveira, M.M.; Andrade, P.B.; Videira, R.A. Mitochondria Research and Neurodegenerative Diseases: On the Track to Understanding the Biological World of High Complexity. Mitochondrion 2022, 65, 67–79. [Google Scholar] [CrossRef] [PubMed]
- Ontario, M.L.; Siracusa, R.; Modafferi, S.; Scuto, M.; Sciuto, S.; Greco, V.; Bertuccio, M.P.; Trovato Salinaro, A.; Crea, R.; Calabrese, E.J.; et al. Potential Prevention and Treatment of Neurodegenerative Disorders by Olive Polyphenols and Hidrox. Mech. Ageing Dev. 2022, 203, 111637. [Google Scholar] [CrossRef]
- Awad, R.; Avital, A.; Sosnik, A. Polymeric Nanocarriers for Nose-to-Brain Drug Delivery in Neurodegenerative Diseases and Neurodevelopmental Disorders. Acta Pharm. Sin. B 2023, 13, 1866–1886. [Google Scholar] [CrossRef] [PubMed]
- Thukral, P.; Chowdhury, R.; Sable, H.; Kaushik, A.; Chaudhary, V. Sustainable Green Synthesized Nanoparticles for Neurodegenerative Diseases Diagnosis and Treatment. Mater. Today Proc. 2023, 73, 323–328. [Google Scholar] [CrossRef]
- Rose, C.R.; Ziemens, D.; Untiet, V.; Fahlke, C. Molecular and Cellular Physiology of Sodium-Dependent Glutamate Transporters. Brain Res. Bull. 2018, 136, 3–16. [Google Scholar] [CrossRef] [PubMed]
- van Onselen, R.; Downing, T.G. Uptake of β-N-Methylamino-L-Alanine (BMAA) into Glutamate-Specific Synaptic Vesicles: Exploring the Validity of the Excitotoxicity Mechanism of BMAA. Neurosci. Lett. 2024, 821, 137593. [Google Scholar] [CrossRef] [PubMed]
- Luo, L.; Li, D.; Xu, X.; Jia, Q.; Li, Z.; Xu, R.; Chen, Z.; Zhao, Y. Synthesis and Neuroprotective Effects of New Genipin Derivatives against Glutamate-Induced Oxidative Damage. Fitoterapia 2023, 169, 105616. [Google Scholar] [CrossRef] [PubMed]
- Neves, D.; Salazar, I.L.; Almeida, R.D.; Silva, R.M. Molecular Mechanisms of Ischemia and Glutamate Excitotoxicity. Life Sci. 2023, 328, 121814. [Google Scholar] [CrossRef]
- Wang, X.; Zhang, F.; Niu, L.; Yan, J.; Liu, H.; Wang, D.; Hui, J.; Dai, H.; Song, J.; Zhang, Z. High-Frequency Repetitive Transcranial Magnetic Stimulation Improves Depressive-like Behaviors in CUMS-Induced Rats by Modulating Astrocyte GLT-1 to Reduce Glutamate Toxicity. J. Affect. Disord. 2024, 348, 265–274. [Google Scholar] [CrossRef] [PubMed]
- Shen, Z.; Xiang, M.; Chen, C.; Ding, F.; Wang, Y.; Shang, C.; Xin, L.; Zhang, Y.; Cui, X. Glutamate Excitotoxicity: Potential Therapeutic Target for Ischemic Stroke. Biomed. Pharmacother. 2022, 151, 113125. [Google Scholar] [CrossRef] [PubMed]
- Velu, L.; Pellerin, L.; Julian, A.; Paccalin, M.; Giraud, C.; Fayolle, P.; Guillevin, R.; Guillevin, C. Early Rise of Glutamate-Glutamine Levels in Mild Cognitive Impairment: Evidence for Emerging Excitotoxicity. J. Neuroradiol. 2024, 51, 168–175. [Google Scholar] [CrossRef]
- Khesmakhi, M.V.; Salimi, Z.; Pourmotabbed, A.; Moradpour, F.; Rezayof, A.; Nedaei, S.E. The Role of Glutamate NMDA Receptors of the Mediodorsal Thalamus in Scopolamine-Induced Amnesia in Rats. Neurosci. Lett. 2024, 820, 137595. [Google Scholar] [CrossRef]
- Iovino, L.; Tremblay, M.E.; Civiero, L. Glutamate-Induced Excitotoxicity in Parkinson’s Disease: The Role of Glial Cells. J. Pharmacol. Sci. 2020, 144, 151–164. [Google Scholar] [CrossRef]
- Burada, A.P.; Vinnakota, R.; Bharti, P.; Dutta, P.; Dubey, N.; Kumar, J. Emerging Insights into the Structure and Function of Ionotropic Glutamate Delta Receptors. Br. J. Pharmacol. 2022, 179, 3612–3627. [Google Scholar] [CrossRef]
- Mori, H.; Mishina, M. Structure and Function of the NMDA Receptor Channel. Neuropharmacology 1995, 34, 1219–1237. [Google Scholar] [CrossRef]
- Murthy, S.E. Glycine-Bound NMDA Receptors Are Stretch-Activated. Trends Neurosci. 2022, 45, 794–795. [Google Scholar] [CrossRef]
- Olivero, G.; Grilli, M.; Marchi, M.; Pittaluga, A. Metamodulation of Presynaptic NMDA Receptors: New Perspectives for Pharmacological Interventions. Neuropharmacology 2023, 234, 109570. [Google Scholar] [CrossRef]
- Li, W.; Kutas, M.; Gray, J.A.; Hagerman, R.H.; Olichney, J.M. The Role of Glutamate in Language and Language Disorders—Evidence from ERP and Pharmacologic Studies. Neurosci. Biobehav. Rev. 2020, 119, 217–241. [Google Scholar] [CrossRef]
- Yi, F.; Mou, T.-C.; Dorsett, K.N.; Volkmann, R.A.; Menniti, F.S.; Sprang, S.R.; Hansen, K.B. Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors. Neuron 2016, 91, 1316–1329. [Google Scholar] [CrossRef] [PubMed]
- Zhou, C.; Tajima, N. Structural Insights into NMDA Receptor Pharmacology. Biochem. Soc. Trans. 2023, 51, 1713–1731. [Google Scholar] [CrossRef]
- Gawande, D.Y.; Shelkar, G.P.; Narasimhan, K.K.S.; Liu, J.; Dravid, S.M. GluN2D Subunit-Containing NMDA Receptors Regulate Reticular Thalamic Neuron Function and Seizure Susceptibility. Neurobiol. Dis. 2023, 181, 106117. [Google Scholar] [CrossRef]
- Mony, L.; Paoletti, P. Mechanisms of NMDA Receptor Regulation. Curr. Opin. Neurobiol. 2023, 83, 102815. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.X.; Shuaib, A. NMDA/NR2BA Selective Antagonists in the Treatment of Ischemic Brain Injury. Curr. Drug Targets CNS Neurol. Disord. 2005, 4, 143–151. [Google Scholar] [CrossRef] [PubMed]
- Bi, X.; Rong, Y.; Chen, J.; Dang, S.; Wang, Z.; Baudry, M. Calpain-Mediated Regulation of NMDA Receptor Structure and Function. Brain Res. 1998, 790, 245–253. [Google Scholar] [CrossRef] [PubMed]
- Jiang, L.; Liu, N.; Zhao, F.; Huang, B.; Kang, D.; Zhan, P.; Liu, X. Discovery of GluN2A Subtype-Selective N-Methyl-d-Aspartate (NMDA) Receptor Ligands. Acta Pharm. Sin. B 2024, 14, 1987–2005. [Google Scholar] [CrossRef]
- Wu, E.; Zhang, J.; Zhang, J.; Zhu, S. Structural Insights into Gating Mechanism and Allosteric Regulation of NMDA Receptors. Curr. Opin. Neurobiol. 2023, 83, 102806. [Google Scholar] [CrossRef] [PubMed]
- Nikam, S.; Meltzer, L. NR2B Selective NMDA Receptor Antagonists. Curr. Pharm. Des. 2005, 8, 845–855. [Google Scholar] [CrossRef]
- Zhang, Z.; Zhang, S.; Fu, P.; Zhang, Z.; Lin, K.; Ko, J.K.-S.; Yung, K.K.-L. Roles of Glutamate Receptors in Parkinson’s Disease. Int. J. Mol. Sci. 2019, 20, 4391. [Google Scholar] [CrossRef] [PubMed]
- Tsai, Y.C.; Huang, S.M.; Peng, H.H.; Lin, S.W.; Lin, S.R.; Chin, T.Y.; Huang, S.M. Imbalance of Synaptic and Extrasynaptic NMDA Receptors Induced by the Deletion of CRMP1 Accelerates Age-Related Cognitive Decline in Mice. Neurobiol. Aging 2024, 135, 48–59. [Google Scholar] [CrossRef] [PubMed]
- Tamborini, L.; Pinto, A.; Mastronardi, F.; Iannuzzi, M.C.; Cullia, G.; Nielsen, B.; De Micheli, C.; Conti, P. 3-Carboxy-Pyrazolinalanine as a New Scaffold for Developing Potent and Selective NMDA Receptor Antagonists. Eur. J. Med. Chem. 2013, 68, 33–37. [Google Scholar] [CrossRef] [PubMed]
- Geter-Douglass, B.; Witkin, J.M. Dizocilpine-like Discriminative Stimulus Effects of Competitive NMDA Receptor Antagonists in Mice. Psychopharmacology 1997, 133, 43–50. [Google Scholar] [CrossRef] [PubMed]
- Kvist, T.; Steffensen, T.B.; Greenwood, J.R.; Mehrzad Tabrizi, F.; Hansen, K.B.; Gajhede, M.; Pickering, D.S.; Traynelis, S.F.; Kastrup, J.S.; Bräuner-Osborne, H. Crystal Structure and Pharmacological Characterization of a Novel N-Methyl-d-Aspartate (NMDA) Receptor Antagonist at the GluN1 Glycine Binding Site. J. Biol. Chem. 2013, 288, 33124–33135. [Google Scholar] [CrossRef]
- Jespersen, A.; Tajima, N.; Fernandez-Cuervo, G.; Garnier-Amblard, E.C.; Furukawa, H. Structural Insights into Competitive Antagonism in NMDA Receptors. Neuron 2014, 81, 366–378. [Google Scholar] [CrossRef] [PubMed]
- Wlaź, P.; Ebert, U.; Potschka, H.; Löscher, W. Electrical but Not Chemical Kindling Increases Sensitivity to Some Phencyclidine-like Behavioral Effects Induced by the Competitive NMDA Receptor Antagonist d-CPPene in Rats. Eur. J. Pharmacol. 1998, 353, 177–189. [Google Scholar] [CrossRef] [PubMed]
- Lind, G.E.; Mou, T.-C.; Tamborini, L.; Pomper, M.G.; De Micheli, C.; Conti, P.; Pinto, A.; Hansen, K.B. Structural Basis of Subunit Selectivity for Competitive NMDA Receptor Antagonists with Preference for GluN2A over GluN2B Subunits. Proc. Natl. Acad. Sci. USA 2017, 114, E6942–E6951. [Google Scholar] [CrossRef] [PubMed]
- Furuya, Y.; Kagaya, T.; Ogura, H.; Nishizawa, Y. Competitive NMDA Receptor Antagonists Disrupt Prepulse Inhibition without Reduction of Startle Amplitude in a Dopamine Receptor-Independent Manner in Mice. Eur. J. Pharmacol. 1999, 364, 133–140. [Google Scholar] [CrossRef] [PubMed]
- Driver, C.; Jackson, T.N.W.; Lagopoulos, J.; Hermens, D.F. Molecular Mechanisms Underlying the N-Methyl-d-Aspartate Receptor Antagonists: Highlighting Their Potential for Transdiagnostic Therapeutics. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2022, 119, 110609. [Google Scholar] [CrossRef] [PubMed]
- Takizawa, S.; Hogan, M.; Hakim, A.M. The Effects of a Competitive NMDA Receptor Antagonist (CGS-19755) on Cerebral Blood Flow and PH in Focal Ischemia. J. Cereb. Blood Flow Metab. 1991, 11, 786–793. [Google Scholar] [CrossRef] [PubMed]
- Willmore, C.B.; Bespalov, A.Y.; Beardsley, P.M. Competitive and Noncompetitive NMDA Antagonist Effects in Rats Trained to Discriminate Lever-Press Counts. Pharmacol. Biochem. Behav. 2001, 69, 493–502. [Google Scholar] [CrossRef] [PubMed]
- Avenet, P.; Léonardon, J.; Besnard, F.; Graham, D.; Depoortere, H.; Scatton, B. Antagonist Properties of Eliprodil and Other NMDA Receptor Antagonists at Rat NR1A/NR2A and NR1A/NR2B Receptors Expressed in Xenopus Oocytes. Neurosci. Lett. 1997, 223, 133–136. [Google Scholar] [CrossRef] [PubMed]
- Danysz, W.; Parsons, C.G.; Karcz-Kubicha, M.; Schwaier, A.; Popik, P.; Wedzony, K.; Lazarewicz, J.; Quack, G. GlycineB Antagonists as Potential Therapeutic Agents. Previous Hopes and Present Reality. Amino Acids 1998, 14, 235–239. [Google Scholar] [CrossRef]
- Mugnaini, M.; Dal Forno, G.; Corsi, M.; Bunnemann, B. Receptor Binding Characteristics of the Novel NMDA Receptor Glycine Site Antagonist [3H]GV150526A in Rat Cerebral Cortical Membranes. Eur. J. Pharmacol. 2000, 391, 233–241. [Google Scholar] [CrossRef]
- Jansen, M.; Dannhardt, G. Antagonists and Agonists at the Glycine Site of the NMDA Receptor for Therapeutic Interventions. Eur. J. Med. Chem. 2003, 38, 661–670. [Google Scholar] [CrossRef] [PubMed]
- Péez-Pinzón, M.A.; Steinberg, G.K. CGS 19755 (Selfotel): A Novel Neuroprotective Agent Against CNS Injury. CNS Drug Rev. 1996, 2, 257–268. [Google Scholar] [CrossRef] [PubMed]
- Sharkey, J.; Ritchie, I.M.; Butcher, S.P.; Kelly, J.S. Comparison of the Patterns of Altered Cerebral Glucose Utilisation Produced by Competitive and Non-Competitive NMDA Receptor Antagonists. Brain Res. 1996, 735, 67–82. [Google Scholar] [CrossRef]
- Bespalov, A.; Kudryashova, M.; Zvartau, E. Prolongation of Morphine Analgesia by Competitive NMDA Receptor Antagonist D-CPPene (SDZ EAA 494) in Rats. Eur. J. Pharmacol. 1998, 351, 299–305. [Google Scholar] [CrossRef] [PubMed]
- Carmack, S.A.; Kim, J.S.; Sage, J.R.; Thomas, A.W.; Skillicorn, K.N.; Anagnostaras, S.G. The Competitive NMDA Receptor Antagonist CPP Disrupts Cocaine-Induced Conditioned Place Preference, but Spares Behavioral Sensitization. Behav. Brain Res. 2013, 239, 155–163. [Google Scholar] [CrossRef]
- Riaza Bermudo-Soriano, C.; Perez-Rodriguez, M.M.; Vaquero-Lorenzo, C.; Baca-Garcia, E. New Perspectives in Glutamate and Anxiety. Pharmacol. Biochem. Behav. 2012, 100, 752–774. [Google Scholar] [CrossRef] [PubMed]
- Liu, P.; Zhang, T.; Chen, Q.; Li, C.; Chu, Y.; Guo, Q.; Zhang, Y.; Zhou, W.; Chen, H.; Zhou, Z.; et al. Biomimetic Dendrimer–Peptide Conjugates for Early Multi-Target Therapy of Alzheimer’s Disease by Inflammatory Microenvironment Modulation. Adv. Mater. 2021, 33, 2100746. [Google Scholar] [CrossRef] [PubMed]
- Jullienne, A.; Montagne, A.; Orset, C.; Lesept, F.; Jane, D.E.; Monaghan, D.T.; Maubert, E.; Vivien, D.; Ali, C. Selective Inhibition of GluN2D-Containing N-Methyl-D-Aspartate Receptors Prevents Tissue Plasminogen Activator-Promoted Neurotoxicity Both in Vitro and in Vivo. Mol. Neurodegener. 2011, 6, 68. [Google Scholar] [CrossRef] [PubMed]
- Mabrouk, O.S.; Mela, F.; Calcagno, M.; Budri, M.; Viaro, R.; Dekundy, A.; Parsons, C.G.; Auberson, Y.P.; Morari, M. GluN2A and GluN2B NMDA Receptor Subunits Differentially Modulate Striatal Output Pathways and Contribute to Levodopa-Induced Abnormal Involuntary Movements in Dyskinetic Rats. ACS Chem. Neurosci. 2013, 4, 808–816. [Google Scholar] [CrossRef] [PubMed]
- Mikics, E.; Toth, M.; Biro, L.; Bruzsik, B.; Nagy, B.; Haller, J. The Role of GluN2B-Containing NMDA Receptors in Short- and Long-Term Fear Recall. Physiol. Behav. 2017, 177, 44–48. [Google Scholar] [CrossRef]
- Papp, M.; Moryl, E. Antidepressant Activity of Non-Competitive and Competitive NMDA Receptor Antagonists in a Chronic Mild Stress Model of Depression. Eur. J. Pharmacol. 1994, 263, 1–7. [Google Scholar] [CrossRef]
- Szakács, R.; Weiczner, R.; Mihály, A.; Krisztin-Péva, B.; Zádor, Z.; Zádor, E. Non-Competitive NMDA Receptor Antagonists Moderate Seizure-Induced c-Fos Expression in the Rat Cerebral Cortex. Brain Res. Bull. 2003, 59, 485–493. [Google Scholar] [CrossRef]
- Tóth, Z.; Mihály, A.; Mátyás, A.; Krisztin-Péva, B. Non-Competitive Antagonists of NMDA and AMPA Receptors Decrease Seizure-Induced c-Fos Protein Expression in the Cerebellum and Protect against Seizure Symptoms in Adult Rats. Acta Histochem. 2018, 120, 236–241. [Google Scholar] [CrossRef]
- Bubser, M.; Keseberg, U.; Notz, P.K.; Schmidt, W.J. Differential Behavioural and Neurochemical Effects of Competitive and Non-Competitive NMDA Receptor Antagonists in Rats. Eur. J. Pharmacol. 1992, 229, 75–82. [Google Scholar] [CrossRef]
- Sun, W.L.; Wessinger, W.D. Characterization of the Non-Competitive Antagonist Binding Site of the NMDA Receptor in Dark Agouti Rats. Life Sci. 2004, 75, 1405–1415. [Google Scholar] [CrossRef]
- Flores, A.J.; Bartlett, M.J.; So, L.Y.; Laude, N.D.; Parent, K.L.; Heien, M.L.; Sherman, S.J.; Falk, T. Differential Effects of the NMDA Receptor Antagonist MK-801 on Dopamine Receptor D1- and D2-Induced Abnormal Involuntary Movements in a Preclinical Model. Neurosci. Lett. 2014, 564, 48–52. [Google Scholar] [CrossRef]
- Berger, M.L.; Rebernik, P. Differential Influence of 7 Cations on 16 Non-Competitive NMDA Receptor Blockers. Bioorg. Med. Chem. Lett. 2015, 25, 4131–4135. [Google Scholar] [CrossRef]
- Marcus, M.M.; Mathé, J.M.; Nomikos, G.G.; Svensson, T.H. Effects of Competitive and Non-Competitive NMDA Receptor Antagonists on Dopamine Output in the Shell and Core Subdivisions of the Nucleus Accumbens. Neuropharmacology 2001, 40, 482–490. [Google Scholar] [CrossRef]
- Blot, K.; Bai, J.; Otani, S. The Effect of Non-Competitive NMDA Receptor Antagonist MK-801 on Neuronal Activity in Rodent Prefrontal Cortex: An Animal Model for Cognitive Symptoms of Schizophrenia. J. Physiol. Paris 2013, 107, 448–451. [Google Scholar] [CrossRef]
- Stuchlík, A.; Vales, K. Systemic Administration of MK-801, a Non-Competitive NMDA-Receptor Antagonist, Elicits a Behavioural Deficit of Rats in the Active Allothetic Place Avoidance (AAPA) Task Irrespectively of Their Intact Spatial Pretraining. Behav. Brain Res. 2005, 159, 163–171. [Google Scholar] [CrossRef]
- Lipton, S.A. Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the Treatment of Acute and Chronic Neurologic Insults. NeuroRx 2004, 1, 101–110. [Google Scholar] [CrossRef]
- Raghavendra Rao, V.L.; Dogan, A.; Todd, K.G.; Bowen, K.K.; Dempsey, R.J. Neuroprotection by Memantine, a Non-Competitive NMDA Receptor Antagonist after Traumatic Brain Injury in Rats. Brain Res. 2001, 911, 96–100. [Google Scholar] [CrossRef]
- Losi, G.; Lanza, M.; Makovec, F.; Artusi, R.; Caselli, G.; Puia, G. Functional in Vitro Characterization of CR 3394: A Novel Voltage Dependent N-Methyl-D-Aspartate (NMDA) Receptor Antagonist. Neuropharmacology 2006, 50, 277–285. [Google Scholar] [CrossRef]
- Geldenhuys, W.J.; Van der Schyf, C.J. Rationally Designed Multi-Targeted Agents Against Neurodegenerative Diseases. Curr. Med. Chem. 2013, 20, 1662–1672. [Google Scholar] [CrossRef]
- Shafiei-Irannejad, V.; Abbaszadeh, S.; Janssen, P.M.L.; Soraya, H. Memantine and Its Benefits for Cancer, Cardiovascular and Neurological Disorders. Eur. J. Pharmacol. 2021, 910, 174455. [Google Scholar] [CrossRef]
- Lin, J.-C.; Chan, M.-H.; Lee, M.-Y.; Chen, Y.-C.; Chen, H.-H. N,N-Dimethylglycine Differentially Modulates Psychotomimetic and Antidepressant-like Effects of Ketamine in Mice. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2016, 71, 7–13. [Google Scholar] [CrossRef]
- Suzuki, A.; Murakami, K.; Tajima, Y.; Hara, H.; Kunugi, A.; Kimura, H. TAK-137, an AMPA Receptor Potentiator with Little Agonistic Effect, Produces Antidepressant-like Effect without Causing Psychotomimetic Effects in Rats. Pharmacol. Biochem. Behav. 2019, 183, 80–86. [Google Scholar] [CrossRef]
- Subramanian, S.; Haroutounian, S.; Palanca, B.J.A.; Lenze, E.J. Ketamine as a Therapeutic Agent for Depression and Pain: Mechanisms and Evidence. J. Neurol. Sci. 2022, 434, 120152. [Google Scholar] [CrossRef]
- Costa, B.M.; Irvine, M.W.; Fang, G.; Eaves, R.J.; Mayo-Martin, M.B.; Skifter, D.A.; Jane, D.E.; Monaghan, D.T. A Novel Family of Negative and Positive Allosteric Modulators of NMDA Receptors. J. Pharmacol. Exp. Ther. 2010, 335, 614–621. [Google Scholar] [CrossRef]
- Sirrieh, R.E.; MacLean, D.M.; Jayaraman, V. A Conserved Structural Mechanism of NMDA Receptor Inhibition: A Comparison of Ifenprodil and Zinc. J. Gen. Physiol. 2015, 146, 173–181. [Google Scholar] [CrossRef]
- Zhang, Z.; Liu, J.; Fan, C.; Mao, L.; Xie, R.; Wang, S.; Yang, M.; Yuan, H.; Yang, X.; Sun, J.; et al. The GluN1/GluN2B NMDA Receptor and Metabotropic Glutamate Receptor 1 Negative Allosteric Modulator Has Enhanced Neuroprotection in a Rat Subarachnoid Hemorrhage Model. Exp. Neurol. 2018, 301, 13–25. [Google Scholar] [CrossRef] [PubMed]
- Zhu, S.; Paoletti, P. Allosteric Modulators of NMDA Receptors: Multiple Sites and Mechanisms. Curr. Opin. Pharmacol. 2015, 20, 14–23. [Google Scholar] [CrossRef]
- Zhu, S.; Stein, R.A.; Yoshioka, C.; Lee, C.-H.; Goehring, A.; Mchaourab, H.S.; Gouaux, E. Mechanism of NMDA Receptor Inhibition and Activation. Cell 2016, 165, 704–714. [Google Scholar] [CrossRef]
- Quan, J.; Yang, H.; Qin, F.; He, Y.; Liu, J.; Zhao, Y.; Ma, C.; Cheng, M. Discovery of Novel Tryptamine Derivatives as GluN2B Subunit-Containing NMDA Receptor Antagonists via Pharmacophore-Merging Strategy with Orally Available Therapeutic Effect of Cerebral Ischemia. Eur. J. Med. Chem. 2023, 253, 115318. [Google Scholar] [CrossRef] [PubMed]
- Mony, L.; Kew, J.N.C.; Gunthorpe, M.J.; Paoletti, P. Allosteric Modulators of NR2B-containing NMDA Receptors: Molecular Mechanisms and Therapeutic Potential. Br. J. Pharmacol. 2009, 157, 1301–1317. [Google Scholar] [CrossRef]
- Zhang, L.; Huang, L.H.; Chen, L.; Hao, D.; Chen, J. Neuroprotection by Tetrahydroxystilbene Glucoside in the MPTP Mouse Model of Parkinson’s Disease. Toxicol. Lett. 2013, 222, 155–163. [Google Scholar] [CrossRef] [PubMed]
- Irvine, M.W.; Fang, G.; Sapkota, K.; Burnell, E.S.; Volianskis, A.; Costa, B.M.; Culley, G.; Collingridge, G.L.; Monaghan, D.T.; Jane, D.E. Investigation of the Structural Requirements for N-Methyl-D-Aspartate Receptor Positive and Negative Allosteric Modulators Based on 2-Naphthoic Acid. Eur. J. Med. Chem. 2019, 164, 471–498. [Google Scholar] [CrossRef]
- Gibb, A.J. Allosteric Antagonist Action at Triheteromeric NMDA Receptors. Neuropharmacology 2022, 202, 108861. [Google Scholar] [CrossRef]
- Markus, A.; Schreiber, J.A.; Goerges, G.; Frehland, B.; Schepmann, D.; Daniliuc, C.; Fröhlich, R.; Seebohm, G.; Wünsch, B. Phenol-Benzoxazolone Bioisosteres of GluN2B-NMDA Receptor Antagonists: Unexpected Rearrangement during Reductive Alkylation with Phenylcyclohexanone. Arch. Pharm. 2022, 355, 2200225. [Google Scholar] [CrossRef]
- Temme, L.; Bechthold, E.; Schreiber, J.A.; Gawaskar, S.; Schepmann, D.; Robaa, D.; Sippl, W.; Seebohm, G.; Wünsch, B. Negative Allosteric Modulators of the GluN2B NMDA Receptor with Phenylethylamine Structure Embedded in Ring-Expanded and Ring-Contracted Scaffolds. Eur. J. Med. Chem. 2020, 190, 112138. [Google Scholar] [CrossRef]
- Hanson, J.E.; Ma, K.; Elstrott, J.; Weber, M.; Saillet, S.; Khan, A.S.; Simms, J.; Liu, B.; Kim, T.A.; Yu, G.-Q.; et al. GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer’s Disease Models. Cell Rep. 2020, 30, 381–396.e4. [Google Scholar] [CrossRef]
- Sapkota, K.; Burnell, E.S.; Irvine, M.W.; Fang, G.; Gawande, D.Y.; Dravid, S.M.; Jane, D.E.; Monaghan, D.T. Pharmacological Characterization of a Novel Negative Allosteric Modulator of NMDA Receptors, UBP792. Neuropharmacology 2021, 201, 108818. [Google Scholar] [CrossRef]
- Hanson, J.E.; Yuan, H.; Perszyk, R.E.; Banke, T.G.; Xing, H.; Tsai, M.C.; Menniti, F.S.; Traynelis, S.F. Therapeutic Potential of N-Methyl-D-Aspartate Receptor Modulators in Psychiatry. Neuropsychopharmacology 2024, 49, 51–66. [Google Scholar] [CrossRef] [PubMed]
- Yao, L.; Zhou, Q. Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators. Neural Plast. 2017, 2017, 2875904. [Google Scholar] [CrossRef] [PubMed]
- Subramaniam, S.; O’Connor, M.J.; Masukawa, L.M.; McGonigle, P. Polyamine Effects on the NMDA Receptor in Human Brain. Exp. Neurol. 1994, 130, 323–330. [Google Scholar] [CrossRef]
- Monaghan, D.T.; Irvine, M.W.; Costa, B.M.; Fang, G.; Jane, D.E. Pharmacological Modulation of NMDA Receptor Activity and the Advent of Negative and Positive Allosteric Modulators. Neurochem. Int. 2012, 61, 581–592. [Google Scholar] [CrossRef]
- Kane, L.T.; Costa, B.M. Identification of Novel Allosteric Modulator Binding Sites in NMDA Receptors: A Molecular Modeling Study. J. Mol. Graph. Model. 2015, 61, 204–213. [Google Scholar] [CrossRef]
- Perszyk, R.; Katzman, B.M.; Kusumoto, H.; Kell, S.A.; Epplin, M.P.; Tahirovic, Y.A.; Moore, R.L.; Menaldino, D.; Burger, P.; Liotta, D.C.; et al. An NMDAR Positive and Negative Allosteric Modulator Series Share a Binding Site and Are Interconverted by Methyl Groups. eLife 2018, 7, e34711. [Google Scholar] [CrossRef] [PubMed]
- Sun, J.Y.; Kumata, K.; Chen, Z.; Zhang, Y.D.; Chen, J.H.; Hatori, A.; Fu, H.L.; Rong, J.; Deng, X.Y.; Yamasaki, T.; et al. Synthesis and Preliminary Evaluation of Novel 11C-Labeled GluN2B-Selective NMDA Receptor Negative Allosteric Modulators. Acta Pharmacol. Sin. 2021, 42, 491–498. [Google Scholar] [CrossRef]
- Auvin, S.; Dozières-Puyravel, B.; Avbersek, A.; Sciberras, D.; Collier, J.; Leclercq, K.; Mares, P.; Kaminski, R.M.; Muglia, P. Radiprodil, a NR2B Negative Allosteric Modulator, from Bench to Bedside in Infantile Spasm Syndrome. Ann. Clin. Transl. Neurol. 2020, 7, 343–352. [Google Scholar] [CrossRef]
- Montastruc, J.L.; Rascol, O.; Senard, J.M. Glutamate Antagonists and Parkinson’s Disease: A Review of Clinical Data. Neurosci. Biobehav. Rev. 1997, 21, 477–480. [Google Scholar] [CrossRef] [PubMed]
- Sasaki, T.; Hashimoto, K.; Niitsu, T.; Hosoda, Y.; Oda, Y.; Shiko, Y.; Ozawa, Y.; Kawasaki, Y.; Kanahara, N.; Shiina, A.; et al. Ifenprodil Tartrate Treatment of Adolescents with Post-Traumatic Stress Disorder: A Double-Blind, Placebo-Controlled Trial. Psychiatry Res. 2022, 311, 114486. [Google Scholar] [CrossRef]
- Swanger, S.A.; Vance, K.M.; Acker, T.M.; Zimmerman, S.S.; DiRaddo, J.O.; Myers, S.J.; Bundgaard, C.; Mosley, C.A.; Summer, S.L.; Menaldino, D.S.; et al. A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons. ACS Chem. Neurosci. 2018, 9, 306–319. [Google Scholar] [CrossRef]
- Rajan, R.; Schepmann, D.; Schreiber, J.A.; Seebohm, G.; Wünsch, B. Synthesis of GluN2A-Selective NMDA Receptor Antagonists with an Electron-Rich Aromatic B-Ring. Eur. J. Med. Chem. 2021, 209, 112939. [Google Scholar] [CrossRef] [PubMed]
- Costa, B.M.; Irvine, M.W.; Fang, G.; Eaves, R.J.; Mayo-Martin, M.B.; Laube, B.; Jane, D.E.; Monaghan, D.T. Structure-Activity Relationships for Allosteric NMDA Receptor Inhibitors Based on 2-Naphthoic Acid. Neuropharmacology 2012, 62, 1730–1736. [Google Scholar] [CrossRef]
- Sapkota, K.; Dore, K.; Tang, K.; Irvine, M.; Fang, G.; Burnell, E.S.; Malinow, R.; Jane, D.E.; Monaghan, D.T. The NMDA Receptor Intracellular C-Terminal Domains Reciprocally Interact with Allosteric Modulators. Biochem. Pharmacol. 2019, 159, 140–153. [Google Scholar] [CrossRef]
- Campbell, I.G.; Gustafson, L.M.; Feinberg, I. The Competitive NMDA Receptor Antagonist CPPene Stimulates NREM Sleep and Eating in Rats. Neuropsychopharmacology 2002, 26, 348–357. [Google Scholar] [CrossRef]
- Baron, B.M.; Siegel, B.W.; Slone, A.L.; Harrison, B.L.; Palfreyman, M.G.; Hurt, S.D. [3H]5,7-Dichlorokynurenic Acid, a Novel Radioligand Labels NMDA Receptor-Associated Glycine Binding Sites. Eur. J. Pharmacol. Mol. Pharmacol. 1991, 206, 149–154. [Google Scholar] [CrossRef]
- Corbett, R.; Dunn, R.W. Effects of 5,7 Dichlorokynurenic Acid on Conflict, Social Interaction and plus Maze Behaviors. Neuropharmacology 1993, 32, 461–466. [Google Scholar] [CrossRef]
- Frankiewicz, T.; Pilc, A.; Parsons, C.G. Differential Effects of NMDA–Receptor Antagonists on Long-Term Potentiation and Hypoxic/Hypoglycaemic Excitotoxicity in Hippocampal Slices. Neuropharmacology 2000, 39, 631–642. [Google Scholar] [CrossRef]
- Hauber, W.; Waldenmeier, M.T. The AMPA Receptor Antagonist GYKI 52466 Reverses the Anti-Cataleptic Effects of the Competitive NMDA Receptor Antagonist CGP 37849. Eur. J. Pharmacol. 1994, 256, 339–342. [Google Scholar] [CrossRef]
- Obrenovitch, T.P.; Hardy, A.M.; Zilkha, E. Effects of L-701,324, a High-Affinity Antagonist at the N-Methyl-D-Aspartate (NMDA) Receptor Glycine Site, on the Rat Electroencephalogram. Naunyn. Schmiedebergs. Arch. Pharmacol. 1997, 355, 779–786. [Google Scholar] [CrossRef] [PubMed]
- Wlaź, P.; Ebert, U.; Löscher, W. Anticonvulsant Effects of Eliprodil Alone or Combined with the Glycine(B) Receptor Antagonist L-701,324 or the Competitive NMDA Antagonist CGP 40116 in the Amygdala Kindling Model in Rats. Neuropharmacology 1999, 38, 243–251. [Google Scholar] [CrossRef]
- Konieczny, J.; Ossowska, K.; Schulze, G.; Coper, H.; Wolfarth, S. L-701,324, a Selective Antagonist at the Glycine Site of the NMDA Receptor, Counteracts Haloperidol-Induced Muscle Rigidity in Rats. Psychopharmacology 1999, 143, 235–243. [Google Scholar] [CrossRef]
- Stone, T.W. Development and Therapeutic Potential of Kynurenic Acid and Kynurenine Derivatives for Neuroprotection. Trends Pharmacol. Sci. 2000, 21, 149–154. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Ji, C.-H.; Wang, Y.; Zhao, J.; Liu, Y.; Tang, W.-Q.; Gu, J.-H.; Jiang, B. Antidepressant-like Activity of L-701324 in Mice: A Behavioral and Neurobiological Characterization. Behav. Brain Res. 2021, 399, 113038. [Google Scholar] [CrossRef] [PubMed]
- Feng, B.; Tse, H.W.; Skifter, D.A.; Morley, R.; Jane, D.E.; Monaghan, D.T. Structure—Activity Analysis of a Novel NR2C/NR2D-Preferring NMDA Receptor Antagonist: 1-(Phenanthrene-2-Carbonyl) Piperazine-2,3-Dicarboxylic Acid. Br. J. Pharmacol. 2004, 141, 508–516. [Google Scholar] [CrossRef] [PubMed]
- Feng, B.; Morley, R.M.; Jane, D.E.; Monaghan, D.T. The Effect of Competitive Antagonist Chain Length on NMDA Receptor Subunit Selectivity. Neuropharmacology 2005, 48, 354–359. [Google Scholar] [CrossRef] [PubMed]
- Bartlett, T.E.; Bannister, N.J.; Collett, V.J.; Dargan, S.L.; Massey, P.V.; Bortolotto, Z.A.; Fitzjohn, S.M.; Bashir, Z.I.; Collingridge, G.L.; Lodge, D. Differential Roles of NR2A and NR2B-Containing NMDA Receptors in LTP and LTD in the CA1 Region of Two-Week Old Rat Hippocampus. Neuropharmacology 2007, 52, 60–70. [Google Scholar] [CrossRef]
- Costa, B.M.; Feng, B.; Tsintsadze, T.S.; Morley, R.M.; Irvine, M.W.; Tsintsadze, V.; Lozovaya, N.A.; Jane, D.E.; Monaghan, D.T. N-Methyl-D-Aspartate (NMDA) Receptor NR2 Subunit Selectivity of a Series of Novel Piperazine-2,3-Dicarboxylate Derivatives: Preferential Blockade of Extrasynaptic NMDA Receptors in the Rat Hippocampal CA3-CA1 Synapse. J. Pharmacol. Exp. Ther. 2009, 331, 618–626. [Google Scholar] [CrossRef]
- Baron, A.; Montagne, A.; Cassé, F.; Launay, S.; Maubert, E.; Ali, C.; Vivien, D. NR2D-Containing NMDA Receptors Mediate Tissue Plasminogen Activator-Promoted Neuronal Excitotoxicity. Cell Death Differ. 2010, 17, 860–871. [Google Scholar] [CrossRef] [PubMed]
- Kinarsky, L.; Feng, B.; Skifter, D.A.; Morley, R.M.; Sherman, S.; Jane, D.E.; Monaghan, D.T. Identification of Subunit- and Antagonist-Specific Amino Acid Residues in the N -Methyl-d-Aspartate Receptor Glutamate-Binding Pocket. J. Pharmacol. Exp. Ther. 2005, 313, 1066–1074. [Google Scholar] [CrossRef] [PubMed]
- Wu, L.J.; Zhuo, M. Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain. Neurotherapeutics 2009, 6, 693–702. [Google Scholar] [CrossRef] [PubMed]
- Lemay-Clermont, J.; Robitaille, C.; Auberson, Y.P.; Bureau, G.; Cyr, M. Blockade of NMDA Receptors 2A Subunit in the Dorsal Striatum Impairs the Learning of a Complex Motor Skill. Behav. Neurosci. 2011, 125, 714–723. [Google Scholar] [CrossRef] [PubMed]
- Santos, M.; D’Amico, D.; Dierssen, M. From Neural to Genetic Substrates of Panic Disorder: Insights from Human and Mouse Studies. Eur. J. Pharmacol. 2015, 759, 127–141. [Google Scholar] [CrossRef] [PubMed]
- Zhu, M.; Zhang, J.; Guo, L.; Yue, R.; Li, S.; Cui, B.; Guo, S.; Niu, Q.; Yu, Y.; Wang, H.; et al. Amorphous Selenium Inhibits Oxidative Stress Injury of Neurons in Vascular Dementia Rats by Activating NMDAR Pathway. Eur. J. Pharmacol. 2023, 955, 175874. [Google Scholar] [CrossRef] [PubMed]
- Urwyler, S.; Campbell, E.; Fricker, G.; Jenner, P.; Lemaire, M.; McAllister, K.H.; Neijt, H.C.; Park, C.K.; Perkins, M.; Rudin, M.; et al. Biphenyl-Derivatives of 2-Amino-7-Phosphono-Heptanoic Acid, a Novel Class of Potent Competitive N-Methyl-D-Aspartate Receptor Antagonists—II. Pharmacological Characterization in Vivo. Neuropharmacology 1996, 35, 655–669. [Google Scholar] [CrossRef] [PubMed]
- Urwyler, S. Biphenyl-Derivatives of 2-Amino-7-Phosphono-Heptanoic Acid, a Novel Class of Potent Competitive N-Methyl-?-Aspartate Receptor Antagonists—I. Pharmacological Characterization in Vitro. Neuropharmacology 1996, 35, 643–654. [Google Scholar] [CrossRef]
- Olsson, S.K.; Linderholm, K.; Erhardt, S.; Engberg, G. P.1.c.039 Increased Midbrain Dopaminergic Firing by the Competitive N-Methyl-D-Aspartate Receptor Antagonist SDZ 220–581. Eur. Neuropsychopharmacol. 2007, 17, S264–S265. [Google Scholar] [CrossRef]
- Bender, C.; de Olmos, S.; Bueno, A.; de Olmos, J.; Lorenzo, A. Comparative Analyses of the Neurodegeneration Induced by the Non-Competitive NMDA-Receptor-Antagonist Drug MK801 in Mice and Rats. Neurotoxicol. Teratol. 2010, 32, 542–550. [Google Scholar] [CrossRef]
- Mellone, M.; Gardoni, F. Modulation of NMDA Receptor at the Synapse: Promising Therapeutic Interventions in Disorders of the Nervous System. Eur. J. Pharmacol. 2013, 719, 75–83. [Google Scholar] [CrossRef]
- Ghasemi, M.; Phillips, C.; Fahimi, A.; McNerney, M.W.; Salehi, A. Mechanisms of Action and Clinical Efficacy of NMDA Receptor Modulators in Mood Disorders. Neurosci. Biobehav. Rev. 2017, 80, 555–572. [Google Scholar] [CrossRef]
- Czarnecka, K.; Chuchmacz, J.; Wójtowicz, P.; Szymański, P. Memantine in Neurological Disorders—Schizophrenia and Depression. J. Mol. Med. 2021, 99, 327–334. [Google Scholar] [CrossRef]
- Hedegaard, M.; Hansen, K.B.; Andersen, K.T.; Bräuner-Osborne, H.; Traynelis, S.F. Molecular Pharmacology of Human NMDA Receptors. Neurochem. Int. 2012, 61, 601–609. [Google Scholar] [CrossRef]
- Rascol, O.; Fabbri, M.; Poewe, W. Amantadine in the Treatment of Parkinson’s Disease and Other Movement Disorders. Lancet Neurol. 2021, 20, 1048–1056. [Google Scholar] [CrossRef]
- Kolesnikova, T.O.; Khatsko, S.L.; Shevyrin, V.A.; Morzherin, Y.Y.; Kalueff, A.V. Effects of a Non-Competitive N-Methyl-d-Aspartate (NMDA) Antagonist, Tiletamine, in Adult Zebrafish. Neurotoxicol. Teratol. 2017, 59, 62–67. [Google Scholar] [CrossRef]
- Cadinu, D.; Grayson, B.; Podda, G.; Harte, M.K.; Doostdar, N.; Neill, J.C. NMDA Receptor Antagonist Rodent Models for Cognition in Schizophrenia and Identification of Novel Drug Treatments, an Update. Neuropharmacology 2018, 142, 41–62. [Google Scholar] [CrossRef]
- Kalmoe, M.C.; Janski, A.M.; Zorumski, C.F.; Nagele, P.; Palanca, B.J.; Conway, C.R. Ketamine and Nitrous Oxide: The Evolution of NMDA Receptor Antagonists as Antidepressant Agents. J. Neurol. Sci. 2020, 412, 116778. [Google Scholar] [CrossRef]
- Kolcheva, M.; Ladislav, M.; Netolicky, J.; Kortus, S.; Rehakova, K.; Krausova, B.H.; Hemelikova, K.; Misiachna, A.; Kadkova, A.; Klima, M.; et al. The Pathogenic N650K Variant in the GluN1 Subunit Regulates the Trafficking, Conductance, and Pharmacological Properties of NMDA Receptors. Neuropharmacology 2023, 222, 109297. [Google Scholar] [CrossRef]
- Kew, J.N.C.; Trube, G.; Kemp, J.A. State-dependent NMDA Receptor Antagonism by Ro 8-4304, a Novel NR2B Selective, Non-competitive, Voltage-independent Antagonist. Br. J. Pharmacol. 1998, 123, 463–472. [Google Scholar] [CrossRef]
- Volgraf, M.; Sellers, B.D.; Jiang, Y.; Wu, G.; Ly, C.Q.; Villemure, E.; Pastor, R.M.; Yuen, P.W.; Lu, A.; Luo, X.; et al. Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design. J. Med. Chem. 2016, 59, 2760–2779. [Google Scholar] [CrossRef]
- Jimenez, E.C. Peptide Antagonists of NMDA Receptors: Structure-Activity Relationships for Potential Therapeutics. Peptides 2022, 153, 170796. [Google Scholar] [CrossRef]
- Löschmann, P.A.; De Groote, C.; Smith, L.; Wüllner, U.; Fischer, G.; Kemp, J.A.; Jenner, P.; Klockgether, T. Antiparkinsonian Activity of Ro 25-6981, a NR2B Subunit Specific NMDA Receptor Antagonist, in Animal Models of Parkinson’s Disease. Exp. Neurol. 2004, 187, 86–93. [Google Scholar] [CrossRef]
- Stan, T.L.; Alvarsson, A.; Branzell, N.; Sousa, V.C.; Svenningsson, P. NMDA Receptor Antagonists Ketamine and Ro25-6981 Inhibit Evoked Release of Glutamate in Vivo in the Subiculum. Transl. Psychiatry 2014, 4, e395. [Google Scholar] [CrossRef]
- Lesuis, S.L.; Lucassen, P.J.; Krugers, H.J. Early Life Stress Impairs Fear Memory and Synaptic Plasticity; a Potential Role for GluN2B. Neuropharmacology 2019, 149, 195–203. [Google Scholar] [CrossRef]
- Gao, X.; Chen, F.; Xu, X.; Liu, J.; Dong, F.; Liu, Y. Ro25-6981 Alleviates Neuronal Damage and Improves Cognitive Deficits by Attenuating Oxidative Stress via the Nrf2/ARE Pathway in Ischemia/Reperfusion Rats. J. Stroke Cerebrovasc. Dis. 2023, 32, 106971. [Google Scholar] [CrossRef]
- Acker, T.M.; Yuan, H.; Hansen, K.B.; Vance, K.M.; Ogden, K.K.; Jensen, H.S.; Burger, P.B.; Mullasseril, P.; Snyder, J.P.; Liotta, D.C.; et al. Mechanism for Noncompetitive Inhibition by Novel GluN2C/D N-Methyl-D-Aspartate Receptor Subunit-Selective Modulators. Mol. Pharmacol. 2011, 80, 782–795. [Google Scholar] [CrossRef]
- Wyllie, D.J.A.; Livesey, M.R.; Hardingham, G.E. Influence of GluN2 Subunit Identity on NMDA Receptor Function. Neuropharmacology 2013, 74, 4–17. [Google Scholar] [CrossRef]
- Pearlstein, E.; Gouty-Colomer, L.A.; Michel, F.J.; Cloarec, R.; Hammond, C. Glutamatergic Synaptic Currents of Nigral Dopaminergic Neurons Follow a Postnatal Developmental Sequence. Front. Cell. Neurosci. 2015, 9, 210. [Google Scholar] [CrossRef]
- Morris, P.G.; Mishina, M.; Jones, S. Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons from Mice Lacking the GluN2D Subunit. Front. Cell. Neurosci. 2018, 12, 354. [Google Scholar] [CrossRef]
- Pálfi, E.; Lévay, G.; Czurkó, A.; Lendvai, B.; Kiss, T. Acute Blockade of NR2C/D Subunit-Containing N-Methyl-D-Aspartate Receptors Modifies Sleep and Neural Oscillations in Mice. J. Sleep Res. 2021, 30, e13257. [Google Scholar] [CrossRef]
- Chizh, B.A.; Headley, P.M.; Tzschentke, T.M. NMDA Receptor Antagonists as Analgesics: Focus on the NR2B Subtype. Trends Pharmacol. Sci. 2001, 22, 636–642. [Google Scholar] [CrossRef]
- He, H.; Yao, J.; Zhang, Y.; Chen, Y.; Wang, K.; Lee, R.J.; Yu, B.; Zhang, X. Solid Lipid Nanoparticles as a Drug Delivery System to across the Blood-Brain Barrier. Biochem. Biophys. Res. Commun. 2019, 519, 385–390. [Google Scholar] [CrossRef]
- Inês Teixeira, M.; Lopes, C.M.; Gonçalves, H.; Catita, J.; Margarida Silva, A.; Rodrigues, F.; Helena Amaral, M.; Costa, P.C. Riluzole-Loaded Lipid Nanoparticles for Brain Delivery: Preparation, Optimization and Characterization. J. Mol. Liq. 2023, 388, 122749. [Google Scholar] [CrossRef]
- Ortega Martínez, E.; Morales Hernández, M.E.; Castillo-González, J.; González-Rey, E.; Ruiz Martínez, M.A. Dopamine-Loaded Chitosan-Coated Solid Lipid Nanoparticles as a Promise Nanocarriers to the CNS. Neuropharmacology 2024, 249, 109871. [Google Scholar] [CrossRef]
- Chen, B.K.; Luna, V.M.; Shannon, M.E.; Hunsberger, H.C.; Mastrodonato, A.; Stackmann, M.; McGowan, J.C.; Rubinstenn, G.; Denny, C.A. Fluoroethylnormemantine, a Novel NMDA Receptor Antagonist, for the Prevention and Treatment of Stress-Induced Maladaptive Behavior. Biol. Psychiatry 2021, 90, 458–472. [Google Scholar] [CrossRef]
- Salabert, A.S.; Fonta, C.; Fontan, C.; Adel, D.; Alonso, M.; Pestourie, C.; Belhadj-Tahar, H.; Tafani, M.; Payoux, P. Radiolabeling of [18F]-Fluoroethylnormemantine and Initial in Vivo Evaluation of This Innovative PET Tracer for Imaging the PCP Sites of NMDA Receptors. Nucl. Med. Biol. 2015, 42, 643–653. [Google Scholar] [CrossRef]
- ReST Therapeutics. First-In-Human (FIH), Single Ascending Dose (SAD) Study of FluoroEthylNorMemantine (FENM). ClinicalTrials.gov. Available online: https://clinicaltrials.gov/study/NCT05921929?tab=table (accessed on 8 April 2024).
- Shram, M.J.; Henningfield, J.E.; Apseloff, G.; Gorodetzky, C.W.; De Martin, S.; Vocci, F.L.; Sapienza, F.L.; Kosten, T.R.; Huston, J.; Buchhalter, A.; et al. The Novel Uncompetitive NMDA Receptor Antagonist Esmethadone (REL-1017) Has No Meaningful Abuse Potential in Recreational Drug Users. Transl. Psychiatry 2023, 13, 192. [Google Scholar] [CrossRef]
- Egunlusi, A.O.; Malan, S.F.; Palchykov, V.A.; Joubert, J. Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-Induced Neurodegeneration. Mini-Rev. Med. Chem. 2024, 24, 1277–1292. [Google Scholar] [CrossRef]
- Gutti, G.; Leifeld, J.; Kakarla, R.; Bajad, N.G.; Ganeshpurkar, A.; Kumar, A.; Krishnamurthy, S.; Klein-Schmidt, C.; Tapken, D.; Hollmann, M.; et al. Discovery of Triazole-Bridged Aryl Adamantane Analogs as an Intriguing Class of Multifunctional Agents for Treatment of Alzheimer’s Disease. Eur. J. Med. Chem. 2023, 259, 115670. [Google Scholar] [CrossRef]
- Zindo, F.T.; Barber, Q.R.; Joubert, J.; Bergh, J.J.; Petzer, J.P.; Malan, S.F. Polycyclic Propargylamine and Acetylene Derivatives as Multifunctional Neuroprotective Agents. Eur. J. Med. Chem. 2014, 80, 122–134. [Google Scholar] [CrossRef]
- Zhang, H.; Wang, Y.; Wang, Y.; Li, X.; Wang, S.; Wang, Z. Recent Advance on Carbamate-Based Cholinesterase Inhibitors as Potential Multifunctional Agents against Alzheimer’s Disease. Eur. J. Med. Chem. 2022, 240, 114606. [Google Scholar] [CrossRef]
- Knez, D.; Diez-Iriepa, D.; Chioua, M.; Gottinger, A.; Denic, M.; Chantegreil, F.; Nachon, F.; Brazzolotto, X.; Skrzypczak-Wiercioch, A.; Meden, A.; et al. 8-Hydroxyquinolylnitrones as Multifunctional Ligands for the Therapy of Neurodegenerative Diseases. Acta Pharm. Sin. B 2023, 13, 2152–2175. [Google Scholar] [CrossRef]
- Guo, J.; Wang, Z.; Liu, R.; Huang, Y.; Zhang, N.; Zhang, R. Memantine, Donepezil, or Combination Therapy—What Is the Best Therapy for Alzheimer’s Disease? A Network Meta-Analysis. Brain Behav. 2020, 10, e01831. [Google Scholar] [CrossRef]
- Iosifescu, D.V.; Jones, A.; O’Gorman, C.; Streicher, C.; Feliz, S.; Fava, M.; Tabuteau, H. Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder. J. Clin. Psychiatry 2022, 83, 22–27. [Google Scholar] [CrossRef]
- Akbar, D.; Rhee, T.G.; Ceban, F.; Ho, R.; Teopiz, K.M.; Cao, B.; Subramaniapillai, M.; Kwan, A.T.H.; Rosenblat, J.D.; McIntyre, R.S. Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials. CNS Drugs 2023, 37, 867–881. [Google Scholar] [CrossRef]
- Yu, G.; Shi, Y.; Cong, S.; Wu, C.; Liu, J.; Zhang, Y.; Liu, H.; Liu, X.; Deng, H.; Tan, Z.; et al. Synthesis and Evaluation of Butylphthalide-Scutellarein Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease. Eur. J. Med. Chem. 2024, 265, 116099. [Google Scholar] [CrossRef]
- McKay, S.; Ryan, T.J.; McQueen, J.; Indersmitten, T.; Marwick, K.F.M.; Hasel, P.; Kopanitsa, M.V.; Baxter, P.S.; Martel, M.A.; Kind, P.C.; et al. The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences. Cell Rep. 2018, 25, 841–851.e4. [Google Scholar] [CrossRef]
- Sun, W.; Hansen, K.B.; Jahr, C.E. Allosteric Interactions between NMDA Receptor Subunits Shape the Developmental Shift in Channel Properties. Neuron 2017, 94, 58–64.e3. [Google Scholar] [CrossRef]
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Egunlusi, A.O.; Joubert, J. NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders. Pharmaceuticals 2024, 17, 639. https://doi.org/10.3390/ph17050639
Egunlusi AO, Joubert J. NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders. Pharmaceuticals. 2024; 17(5):639. https://doi.org/10.3390/ph17050639
Chicago/Turabian StyleEgunlusi, Ayodeji Olatunde, and Jacques Joubert. 2024. "NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders" Pharmaceuticals 17, no. 5: 639. https://doi.org/10.3390/ph17050639
APA StyleEgunlusi, A. O., & Joubert, J. (2024). NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders. Pharmaceuticals, 17(5), 639. https://doi.org/10.3390/ph17050639