N-Methyl-D-Aspartate (NMDA) Receptor Antagonists and their Pharmacological Implication: A Medicinal Chemistry-oriented Perspective Outline
- Authors: Rana V.1, Ghosh S.1, Bhatt A.1, Bisht D.1, Joshi G.2, Purohit P.1
-
Affiliations:
- Department of Pharmacy, Graphic Era Hill University
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University)
- Issue: Vol 31, No 29 (2024)
- Pages: 4725-4744
- Section: Anti-Infectives and Infectious Diseases
- URL: https://hum-ecol.ru/0929-8673/article/view/645011
- DOI: https://doi.org/10.2174/0109298673288031240405061759
- ID: 645011
Cite item
Full Text
Abstract
N-methyl-D-aspartate (NMDA) receptors, i.e., inotropic glutamate receptors, are important in synaptic plasticity, brain growth, memory, and learning. The activation of NMDA is done by neurotransmitter glutamate and co-agonist (glycine or D-serine) binding. However, the over-activation of NMDA elevates the intracellular calcium influx, which causes various neurological diseases and disorders. Therefore, to prevent excitotoxicity and neuronal death, inhibition of NMDA must be done using its antagonist. This review delineates the structure of subunits of NMDA and the conformational changes induced after the binding of agonists (glycine and D-serine) and antagonists (ifenprodil, etc.). Additionally, reported NMDA antagonists from different sources, such as synthetic, semisynthetic, and natural resources, are explained by their mechanism of action and pharmacological role. The comprehensive report also addresses the chemical spacing of NMDA inhibitors and in-vivo and in-vitro models to test NMDA antagonists. Since the Blood-Brain Barrier (BBB) is the primary membrane that prevents the penetration of a wide variety of drug molecules, we also elaborate on the medicinal chemistry approach to improve the effectiveness of their antagonists.
About the authors
Vikas Rana
Department of Pharmacy, Graphic Era Hill University
Email: info@benthamscience.net
Shayantan Ghosh
Department of Pharmacy, Graphic Era Hill University
Email: info@benthamscience.net
Akanksha Bhatt
Department of Pharmacy, Graphic Era Hill University
Email: info@benthamscience.net
Damini Bisht
Department of Pharmacy, Graphic Era Hill University
Email: info@benthamscience.net
Gaurav Joshi
Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University)
Email: info@benthamscience.net
Priyank Purohit
Department of Pharmacy, Graphic Era Hill University
Author for correspondence.
Email: info@benthamscience.net
References
- Reiner, A.; Levitz, J. Glutamatergic signaling in the central nervous system: Ionotropic and metabotropic receptors in concert. Neuron, 2018, 98(6), 1080-1098. doi: 10.1016/j.neuron.2018.05.018 PMID: 29953871
- Chen, K.; Yang, L.N.; Lai, C.; Liu, D.; Zhu, L.Q. Role of Grina/Nmdara1 in the central nervous system diseases. Curr. Neuropharmacol., 2020, 18(9), 861-867. doi: 10.2174/1570159X18666200303104235 PMID: 32124700
- Wang, J.X.; Furukawa, H. Dissecting diverse functions of NMDA receptors by structural biology. Curr. Opin. Struct. Biol., 2019, 54, 34-42. doi: 10.1016/j.sbi.2018.12.009 PMID: 30703613
- Mayor, D.; Tymianski, M. Neurotransmitters in the mediation of cerebral ischemic injury. Neuropharmacology, 2018, 134(Pt B), 178-188. doi: 10.1016/j.neuropharm.2017.11.050 PMID: 29203179
- Sachana, M.; Rolaki, A.; Price, B.A. Development of the adverse outcome pathway (AOP): Chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. Toxicol. Appl. Pharmacol., 2018, 354, 153-175. doi: 10.1016/j.taap.2018.02.024 PMID: 29524501
- Ugale, V; Dhote, A; Narwade, R; Khadse, S; Reddy, PN; Shirkhedkar, A GluN2B/N-methyl-d-aspartate receptor antagonists: Advances in design, synthesis, and pharmacological evaluation studies. CNS Neurol. Disord. Drug Targets, 2021, 20(9), 822-862.
- Rajani, V.; Sengar, A.S.; Salter, M.W. Tripartite signalling by NMDA receptors. Mol. Brain, 2020, 13(1), 23. doi: 10.1186/s13041-020-0563-z PMID: 32070387
- Vieira, M.; Yong, X.L.H.; Roche, K.W.; Anggono, V. Regulation of NMDA glutamate receptor functions by the GluN2 subunits. J. Neurochem., 2020, 154(2), 121-143. doi: 10.1111/jnc.14970 PMID: 31978252
- Regan, M.C.; Hernandez, R.A.; Furukawa, H. A structural biology perspective on NMDA receptor pharmacology and function. Curr. Opin. Struct. Biol., 2015, 33, 68-75. doi: 10.1016/j.sbi.2015.07.012 PMID: 26282925
- Grand, T.; Abi Gerges, S.; David, M.; Diana, M.A.; Paoletti, P. Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nat. Commun., 2018, 9(1), 4769. doi: 10.1038/s41467-018-07236-4 PMID: 30425244
- Romero-Hernandez, A.; Simorowski, N.; Karakas, E.; Furukawa, H. Molecular basis for subtype specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino-terminal domain. Neuron, 2016, 92(6), 1324-1336. doi: 10.1016/j.neuron.2016.11.006 PMID: 27916457
- Stroebel, D.; Mony, L.; Paoletti, P. Glycine agonism in ionotropic glutamate receptors. Neuropharmacology, 2021, 193, 108631. doi: 10.1016/j.neuropharm.2021.108631 PMID: 34058193
- Tian, M.; Ye, S. Allosteric regulation in NMDA receptors revealed by the genetically encoded photo-cross-linkers. Sci. Rep., 2016, 6(1), 34751. doi: 10.1038/srep34751 PMID: 27713495
- Chou, T.H.; Epstein, M.; Michalski, K.; Fine, E.; Biggin, P.C.; Furukawa, H. Structural insights into binding of therapeutic channel blockers in NMDA receptors. Nat. Struct. Mol. Biol., 2022, 29(6), 507-518. doi: 10.1038/s41594-022-00772-0 PMID: 35637422
- Painuli, S.; Semwal, P.; Zam, W.; Taheri, Y.; Ezzat, S.M.; Zuo, P.; Li, L.; Kumar, D.; Rad, S.J.; Martins, C.N. NMDA inhibitors: A potential contrivance to assist in management of Alzheimers disease. Comb. Chem. High Throughput Screen., 2023, 26(12), 2099-2112. doi: 10.2174/1386207325666220428112541 PMID: 36476432
- Zhu, S.; Paoletti, P. Allosteric modulators of NMDA receptors: Multiple sites and mechanisms. Curr. Opin. Pharmacol., 2015, 20, 14-23. doi: 10.1016/j.coph.2014.10.009 PMID: 25462287
- Warnet, X.L.; Krog, B.H.; Quispe, S.O.G.; Poulsen, H.; Kjaergaard, M. The C-terminal domains of the NMDA receptor: How intrinsically disordered tails affect signalling, plasticity and disease. Eur. J. Neurosci., 2021, 54(8), 6713-6739. doi: 10.1111/ejn.14842 PMID: 32464691
- Haddow, K.; Kind, P.C.; Hardingham, G.E. NMDA receptor C-terminal domain signalling in development, maturity, and disease. Int. J. Mol. Sci., 2022, 23(19), 11392. doi: 10.3390/ijms231911392 PMID: 36232696
- Wilbek, T.S.; Skovgaard, T.; Sorrell, F.J.; Knapp, S.; Berthelsen, J.; Strømgaard, K. Identification and characterization of a small-molecule inhibitor of death-associated protein kinase 1. ChemBioChem, 2015, 16(1), 59-63. doi: 10.1002/cbic.201402512 PMID: 25382253
- 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. doi: 10.1016/j.bcp.2018.11.018 PMID: 30503374
- Paoletti, P.; Neyton, J. NMDA receptor subunits: Function and pharmacology. Curr. Opin. Pharmacol., 2007, 7(1), 39-47. doi: 10.1016/j.coph.2006.08.011 PMID: 17088105
- Gonda, X. Basic pharmacology of NMDA receptors. Curr. Pharm. Des., 2012, 18(12), 1558-1567. doi: 10.2174/138161212799958521 PMID: 22280436
- 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(3), 704-714. doi: 10.1016/j.cell.2016.03.028 PMID: 27062927
- Ferreira, I.L.; Bajouco, L.M.; Mota, S.I.; Auberson, Y.P.; Oliveira, C.R.; Rego, A.C. Amyloid beta peptide 142 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-d-aspartate receptors in cortical cultures. Cell Calcium, 2012, 51(2), 95-106. doi: 10.1016/j.ceca.2011.11.008 PMID: 22177709
- Saura, CA; Valero, J. The role of CREB signaling in Alzheimer's disease and other cognitive disorders. Rev Neurosci, 2011, 22(2), 153-169. doi: 10.1515/rns.2011.018
- Alberini, C.M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev., 2009, 89(1), 121-145. doi: 10.1152/physrev.00017.2008 PMID: 19126756
- Du, H.; Guo, L.; Wu, X.; Sosunov, A.A.; McKhann, G.M.; Chen, J.X.; Yan, S.S. Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim. Biophys. Acta Mol. Basis Dis., 2014, 1842(12), 2517-2527. doi: 10.1016/j.bbadis.2013.03.004 PMID: 23507145
- Zhang, Y.; Li, P.; Feng, J.; Wu, M. Dysfunction of NMDA receptors in Alzheimers disease. Neurol. Sci., 2016, 37(7), 1039-1047. doi: 10.1007/s10072-016-2546-5 PMID: 26971324
- Sonsalla, P.K.; Albers, D.S.; Zeevalk, G.D. Role of glutamate in neurodegeneration of dopamine neurons in several animal models of parkinsonism. Amino Acids, 1998, 14(1-3), 69-74. doi: 10.1007/BF01345245 PMID: 9871444
- Meredith, G.E.; Totterdell, S.; Beales, M.; Meshul, C.K. Impaired glutamate homeostasis and programmed cell death in a chronic MPTP mouse model of Parkinsons disease. Exp. Neurol., 2009, 219(1), 334-340. doi: 10.1016/j.expneurol.2009.06.005 PMID: 19523952
- Erickson, C.A.; Posey, D.J.; Stigler, K.A.; Mullett, J.; Katschke, A.R.; McDougle, C.J. A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology, 2007, 191(1), 141-147. doi: 10.1007/s00213-006-0518-9 PMID: 17016714
- Reiff, M. Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J. Dev. Behav. Pediatr., 2001, 22(5), 339. doi: 10.1097/00004703-200110000-00018
- Harris, B.R.; Prendergast, M.A.; Gibson, D.A.; Rogers, D.T.; Blanchard, J.A.; Holley, R.C.; Fu, M.C.; Hart, S.R.; Pedigo, N.W.; Littleton, J.M. Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol. Clin. Exp. Res., 2002, 26(12), 1779-1793. doi: 10.1111/j.1530-0277.2002.tb02484.x PMID: 12500101
- Altinoz, M.A.; Ozpinar, A.; Hacker, E.; Ozpinar, A. A hypothetical proposal to employ meperidine and tamoxifen in treatment of glioblastoma. Role of P-glycoprotein, ceramide and metabolic pathways. Clin. Neurol. Neurosurg., 2022, 215, 107208. doi: 10.1016/j.clineuro.2022.107208 PMID: 35316699
- Fogaça, M.V.; Fukumoto, K.; Franklin, T.; Liu, R.J.; Duman, C.H.; Vitolo, O.V.; Duman, R.S. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology, 2019, 44(13), 2230-2238. doi: 10.1038/s41386-019-0501-x PMID: 31454827
- Antoniu, S.A.; Apostu, M.; Alexinschi, O.; Mosoiu, D. Dextromethorphan for chronic neuropathic pain in palliative care. Expert Rev. Qual. Life Cancer Care, 2017, 2(1), 5-12. doi: 10.1080/23809000.2017.1264259
- Ostadhadi, S.; Javidan, N.A.; Chamanara, M.; Akbarian, R.; Imran-Khan, M.; Ghasemi, M.; Dehpour, A.R. Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test. Brain Res. Bull., 2017, 134, 136-141. doi: 10.1016/j.brainresbull.2017.07.016 PMID: 28754288
- Thigpen, J.C.; Odle, B.L.; Harirforoosh, S. Opioids: A review of pharmacokinetics and pharmacodynamics in neonates, infants, and children. Eur. J. Drug Metab. Pharmacokinet., 2019, 44(5), 591-609. doi: 10.1007/s13318-019-00552-0 PMID: 31006834
- Tetteh, H.; Lee, M.; Lau, C.G.; Yang, S.; Yang, S. Tinnitus: Prospects for pharmacological interventions with a seesaw model. Neuroscientist, 2018, 24(4), 353-367. doi: 10.1177/1073858417733415 PMID: 29283017
- Gatius, T.M.; Hill, L.X.; Rio, M.L.; Castarlenas, L.; Fabius, S.; Santana, N.; Vilaró, M.T.; Artigas, F.; Scorza, M.C.; Castañé, A. Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models. Neuropharmacology, 2022, 213, 109079. doi: 10.1016/j.neuropharm.2022.109079 PMID: 35561792
- Novakov, I.A.; Sheikin, D.S.; Navrotskii, M.B.; Mkrtchyan, A.S.; Brunilina, L.L.; Balakin, K.V. Dexoxadrol and its bioisosteres: Structure, synthesis, and pharmacological activity. Russ. Chem. Bull., 2020, 69(9), 1625-1671. doi: 10.1007/s11172-020-2946-9
- Farber, N.B.; Jiang, X-P.; Heinkel, C.; Nemmers, B. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol. Psychiatry, 2002, 7(7), 726-733. doi: 10.1038/sj.mp.4001087 PMID: 12192617
- Turner, E.H. Esketamine for treatment-resistant depression: Seven concerns about efficacy and FDA approval. Lancet Psychiatry, 2019, 6(12), 977-979. doi: 10.1016/S2215-0366(19)30394-3 PMID: 31680014
- Taylor, C.P.; Traynelis, S.F.; Siffert, J.; Pope, L.E.; Matsumoto, R.R. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol. Ther., 2016, 164, 170-182. doi: 10.1016/j.pharmthera.2016.04.010 PMID: 27139517
- Shaibani, A.I.; Pope, L.E.; Thisted, R.; Hepner, A. Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: A double-blind, placebo-controlled, multicenter study. Pain Med., 2012, 13(2), 243-254. doi: 10.1111/j.1526-4637.2011.01316.x PMID: 22314263
- Cummings, J.L.; Lyketsos, C.G.; Peskind, E.R.; Porsteinsson, A.P.; Mintzer, J.E.; Scharre, D.W.; De La Gandara, J.E.; Agronin, M.; Davis, C.S.; Nguyen, U.; Shin, P.; Tariot, P.N.; Siffert, J. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: A randomized clinical trial. JAMA, 2015, 314(12), 1242-1254. doi: 10.1001/jama.2015.10214 PMID: 26393847
- Kawai, N.; Niwa, A.; Abe, T. Spider venom contains specific receptor blocker of glutaminergic synapses. Brain Res., 1982, 247(1), 169-171. doi: 10.1016/0006-8993(82)91044-7 PMID: 6127145
- Takeuchi, A.; Onodera, K. Effects of kainic acid on the glutamate receptors of the crayfish muscle. Neuropharmacology, 1975, 14(9), 619-625. doi: 10.1016/0028-3908(75)90084-2 PMID: 1178118
- Shinozaki, H.; Shibuya, I. Potentiation of glutamate-induced depolarization by kainic acid in the crayfish opener muscle. Neuropharmacology, 1974, 13(10-11), 1057-1065. doi: 10.1016/0028-3908(74)90096-3 PMID: 4437724
- Serefko, A.; Szopa, A.; Wlaź, A.; Wośko, S.; Wlaź, P.; Poleszak, E. Synergistic antidepressant-like effect of the joint administration of caffeine and NMDA receptor ligands in the forced swim test in mice. J. Neural Transm., 2016, 123(4), 463-472. doi: 10.1007/s00702-015-1467-4 PMID: 26510772
- Alasmari, F. Caffeine induces neurobehavioral effects through modulating neurotransmitters. Saudi Pharm. J., 2020, 28(4), 445-451. doi: 10.1016/j.jsps.2020.02.005 PMID: 32273803
- Chindo, B.A.; Howes, M.J.R.; Abuhamdah, S.; Yakubu, M.I.; Ayuba, G.I.; Battison, A.; Chazot, P.L. New insights into the anticonvulsant effects of essential oil from Melissa officinalis L. (Lemon Balm). Front. Pharmacol., 2021, 12, 760674. doi: 10.3389/fphar.2021.760674 PMID: 34721045
- Rinaldi, T.; Kulangara, K.; Antoniello, K.; Markram, H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc. Natl. Acad. Sci., 2007, 104(33), 13501-13506. doi: 10.1073/pnas.0704391104 PMID: 17675408
- Kim, K.C.; Lee, D.K.; Go, H.S.; Kim, P.; Choi, C.S.; Kim, J.W.; Jeon, S.J.; Song, M.R.; Shin, C.Y. Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Mol. Neurobiol., 2014, 49(1), 512-528. doi: 10.1007/s12035-013-8535-2 PMID: 24030726
- Kang, J.; Kim, E. Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors. Front. Mol. Neurosci., 2015, 8, 17. doi: 10.3389/fnmol.2015.00017 PMID: 26074764
- Lenart, J.; Augustyniak, J.; Lazarewicz, J.W.; Zieminska, E. Altered expression of glutamatergic and GABAergic genes in the valproic acid-induced rat model of autism: A screening test. Toxicology, 2020, 440, 152500. doi: 10.1016/j.tox.2020.152500 PMID: 32428529
- Kumar, H.; Sharma, B. Memantine ameliorates autistic behavior, biochemistry & blood brain barrier impairments in rats. Brain Res. Bull., 2016, 124, 27-39. doi: 10.1016/j.brainresbull.2016.03.013 PMID: 27034117
- Burket, J.A.; Deutsch, S.I. Metabotropic functions of the NMDA receptor and an evolving rationale for exploring NR2A-selective positive allosteric modulators for the treatment of autism spectrum disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2019, 90, 142-160. doi: 10.1016/j.pnpbp.2018.11.017 PMID: 30481555
- Zhan, Y.; Xia, J.; Wang, X. Effects of glutamate-related drugs on anxiety and compulsive behavior in rats with obsessive-compulsive disorder. Int. J. Neurosci., 2020, 130(6), 551-560. doi: 10.1080/00207454.2019.1684276 PMID: 31680595
- Su, L.D.; Wang, N.; Han, J.; Shen, Y. Group 1 metabotropic glutamate receptors in neurological and psychiatric diseases: Mechanisms and prospective. Neuroscientist, 2022, 28(5), 453-468. doi: 10.1177/10738584211021018 PMID: 34088252
- Maksymetz, J.; Moran, S.P.; Conn, P.J. Targeting metabotropic glutamate receptors for novel treatments of schizophrenia. Mol. Brain, 2017, 10(1), 15. doi: 10.1186/s13041-017-0293-z PMID: 28446243
- Varnamkhasti, B.S.; Jafari, S.; Taghavi, F.; Alaei, L.; Izadi, Z.; Lotfabadi, A.; Dehghanian, M.; Jaymand, M.; Derakhshankhah, H.; Saboury, A.A. Cell-penetrating peptides: As a promising theranostics strategy to circumvent the blood-brain barrier for CNS diseases. Curr. Drug Deliv., 2020, 17(5), 375-386. doi: 10.2174/1567201817666200415111755 PMID: 32294035
- Barnabas, W. Drug targeting strategies into the brain for treating neurological diseases. J. Neurosci. Methods, 2019, 311, 133-146. doi: 10.1016/j.jneumeth.2018.10.015 PMID: 30336221
- Krizbai, I.; Nyúl-Tóth, Á.; Bauer, H.C.; Farkas, A.; Traweger, A.; Haskó, J.; Bauer, H.; Wilhelm, I. Pharmaceutical targeting of the brain. Curr. Pharm. Des., 2016, 22(35), 5442-5462. doi: 10.2174/1381612822666160726144203 PMID: 27464716
- Botti, G.; Dalpiaz, A.; Pavan, B. Targeting systems to the brain obtained by merging prodrugs, nanoparticles, and nasal administration. Pharmaceutics, 2021, 13(8), 1144. doi: 10.3390/pharmaceutics13081144 PMID: 34452105
- Grabrucker, A.M.; Chhabra, R.; Belletti, D.; Forni, F.; Vandelli, M.A.; Ruozi, B.; Tosi, G. Nanoparticles as blood-brain barrier permeable CNS targeted drug delivery systems. In: The Blood Brain Barrier (BBB); Springer, 2014; pp. 71-89.
- Vilella, A.; Ruozi, B.; Belletti, D.; Pederzoli, F.; Galliani, M.; Semeghini, V.; Forni, F.; Zoli, M.; Vandelli, M.; Tosi, G. Endocytosis of nanomedicines: The case of glycopeptide engineered PLGA nanoparticles. Pharmaceutics, 2015, 7(2), 74-89. doi: 10.3390/pharmaceutics7020074 PMID: 26102358
- Begley, DJ; Bellettato, CM; Scarpa, M Central nervous system aspects, neurodegeneration, and the blood-brain barrier. In: Lysosomal Storage Disorders: A Practical Guide, 2nd ed.; Wiley, 2022.
- Wang, T.; Wu, M.B.; Zhang, R.H.; Chen, Z.J.; Hua, C.; Lin, J.P.; Yang, L.R. Advances in computational structure-based drug design and application in drug discovery. Curr. Top. Med. Chem., 2015, 16(9), 901-916. doi: 10.2174/1568026615666150825142002 PMID: 26303430
- Tajima, N.; Simorowski, N.; Yovanno, R.A.; Regan, M.C.; Michalski, K.; Gómez, R.; Lau, A.Y.; Furukawa, H. Development and characterization of functional antibodies targeting NMDA receptors. Nat. Commun., 2022, 13(1), 923. doi: 10.1038/s41467-022-28559-3 PMID: 35177668
- Stępnicki, P.; Kondej, M.; Koszła, O.; Żuk, J.; Kaczor, A.A. Multi-targeted drug design strategies for the treatment of schizophrenia. Expert Opin. Drug Discov., 2021, 16(1), 101-114. doi: 10.1080/17460441.2020.1816962 PMID: 32915109
- Rosini, M.; Simoni, E.; Minarini, A.; Melchiorre, C. Multi- target design strategies in the context of Alzheimers disease: Acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochem. Res., 2014, 39(10), 1914-1923. doi: 10.1007/s11064-014-1250-1 PMID: 24493627
- Pardridge, W.M. Bloodbrain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody. Expert Opin. Drug Deliv., 2015, 12(2), 207-222. doi: 10.1517/17425247.2014.952627 PMID: 25138991
- Chang, R.; Knox, J.; Chang, J.; Derbedrossian, A.; Vasilevko, V.; Cribbs, D.; Boado, R.J.; Pardridge, W.M.; Sumbria, R.K. Bloodbrain barrier penetrating biologic TNF-α inhibitor for Alzheimers disease. Mol. Pharm., 2017, 14(7), 2340-2349. doi: 10.1021/acs.molpharmaceut.7b00200 PMID: 28514851
- Timothy, J. Combination of a NMDA receptor antagonist and a MAO-inhibitor or a GADPH-inhibitor for the treatment of central nervous system-related conditions. EP Patent 1715843A1, 2011.
- Guitton, M.; Puel, J.L.; Pujol, R. Use of an NMDA receptor antagonist for the treatment of tinnitus induced by cochlear excitotoxicity. KR Patent 101429735B1, 2005.
- R. U. S. A. Data, S. Gupta, and G. Samoriski, "(12) Patent Application Publication (10) Pub. No.: US 2010 / 0076073 A1," vol. 1, no. 19, 2010.
- Buratti, S.; Giacheri, E.; Palmieri, A.; Tibaldi, J.; Brisca, G.; Riva, A.; Striano, P.; Mancardi, M.M.; Nobili, L.; Moscatelli, A. Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children. Epilepsia, 2023, 64(4), 797-810. doi: 10.1111/epi.17550 PMID: 36792542
- Vasquez, A.; Gaínza-Lein, M.; Sánchez Fernández, I.; Abend, N.S.; Anderson, A.; Brenton, J.N.; Carpenter, J.L.; Chapman, K.; Clark, J.; Gaillard, W.D.; Glauser, T.; Goldstein, J.; Goodkin, H.P.; Lai, Y.C.; Loddenkemper, T.; McDonough, T.L.; Mikati, M.A.; Nayak, A.; Payne, E.; Riviello, J.; Tchapyjnikov, D.; Topjian, A.A.; Wainwright, M.S.; Tasker, R.C. Hospital emergency treatment of convulsive status epilepticus: Comparison of pathways from ten pediatric research centers. Pediatr. Neurol., 2018, 86, 33-41. doi: 10.1016/j.pediatrneurol.2018.06.004 PMID: 30075875
- Singh, A.; Stredny, C.M.; Loddenkemper, T. Pharmacotherapy for pediatric convulsive status epilepticus. CNS Drugs, 2020, 34(1), 47-63. doi: 10.1007/s40263-019-00690-8 PMID: 31879852
- Alkhachroum, A.; Der-Nigoghossian, C.A.; Mathews, E.; Massad, N.; Letchinger, R.; Doyle, K.; Chiu, W.T.; Kromm, J.; Rubinos, C.; Velazquez, A.; Roh, D.; Agarwal, S.; Park, S.; Connolly, E.S.; Claassen, J. Ketamine to treat super-refractory status epilepticus. Neurology, 2020, 95(16), e2286-e2294. doi: 10.1212/WNL.0000000000010611 PMID: 32873691
- Jacobwitz, M.; Mulvihill, C.; Kaufman, M.C.; Gonzalez, A.K.; Resendiz, K.; MacDonald, J.M.; Francoeur, C.; Helbig, I.; Topjian, A.A.; Abend, N.S. Ketamine for management of neonatal and pediatric refractory status epilepticus. Neurology, 2022, 99(12), e1227-e1238. doi: 10.1212/WNL.0000000000200889 PMID: 35817569
- Rosati, A.; LErario, M.; Bianchi, R.; Olivotto, S.; Battaglia, D.I.; Darra, F.; Biban, P.; Biggeri, A.; Catelan, D.; Danieli, G.; Mondardini, M.C.; Cordelli, D.M.; Amigoni, A.; Cesaroni, E.; Conio, A.; Costa, P.; Lombardini, M.; Meleleo, R.; Pugi, A.; Tornaboni, E.E.; Santarone, M.E.; Vittorini, R.; Sartori, S.; Marini, C.; Vigevano, F.; Mastrangelo, M.; Pulitanò, S.M.; Izzo, F.; Fusco, L. KETASER01 protocol: What went right and what went wrong. Epilepsia Open, 2022, 7(3), 532-540. doi: 10.1002/epi4.12627 PMID: 35833327
- Sampietro, A.; Pérez-Areales, F.J.; Martínez, P.; Arce, E.M.; Galdeano, C.; Torrero, M.D. Unveiling the multitarget anti-Alzheimer drug discovery landscape: A bibliometric analysis. Pharmaceuticals, 2022, 15(5), 545. doi: 10.3390/ph15050545 PMID: 35631371
- Potasiewicz, A.; Krawczyk, M.; Gzielo, K.; Popik, P.; Nikiforuk, A. Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors enhance procognitive effects of conventional anti-Alzheimer drugs in scopolamine-treated rats. Behav. Brain Res., 2020, 385, 112547. doi: 10.1016/j.bbr.2020.112547 PMID: 32087183
- Albertini, C.; Salerno, A.; de Pinheiro, S.M.P.; Bolognesi, M.L. From combinations to multitarget-directed ligands: A continuum in Alzheimers disease polypharmacology. Med. Res. Rev., 2021, 41(5), 2606-2633. doi: 10.1002/med.21699 PMID: 32557696
- Lista, S.; Vergallo, A.; Teipel, S.J.; Lemercier, P.; Giorgi, F.S.; Gabelle, A.; Garaci, F.; Mercuri, N.B.; Babiloni, C.; Gaire, B.P.; Koronyo, Y.; Hamaoui, K.M.; Hampel, H.; Nisticò, R. Determinants of approved acetylcholinesterase inhibitor response outcomes in Alzheimers disease: Relevance for precision medicine in neurodegenerative diseases. Ageing Res. Rev., 2023, 84, 101819. doi: 10.1016/j.arr.2022.101819 PMID: 36526257
- McClure, E.W.; Daniels, R.N. Classics in chemical neuroscience: Dextromethorphan (DXM). ACS Chem. Neurosci., 2023, 14(12), 2256-2270. doi: 10.1021/acschemneuro.3c00088 PMID: 37290117
- Silva, A.R.; Oliveira, D.R.J. Pharmacokinetics and pharmacodynamics of dextromethorphan: Clinical and forensic aspects. Drug Metab. Rev., 2020, 52(2), 258-282. doi: 10.1080/03602532.2020.1758712 PMID: 32393072
- Campos-Mañas, M.C.; Cuevas, S.M.; Ferrer, I.; Thurman, E.M.; Pérez, S.J.A.; Agüera, A. Determination of dextromethorphan and dextrorphan solar photo-transformation products by LC/Q-TOF-MS: Laboratory scale experiments and real water samples analysis. Environ. Pollut., 2020, 265(Pt A), 114722. doi: 10.1016/j.envpol.2020.114722 PMID: 32454378
- Chia, J.S.M.; Izham, N.A.M.; Farouk, A.A.O.; Sulaiman, M.R.; Mustafa, S.; Hutchinson, M.R.; Perimal, E.K. Zerumbone modulates α2A-adrenergic, TRPV1, and NMDA NR2B receptors plasticity in CCI-induced neuropathic pain in vivo and LPS-induced SH-SY5Y neuroblastoma in vitro models. Front. Pharmacol., 2020, 11, 92. doi: 10.3389/fphar.2020.00092 PMID: 32194397
- Halliwell, R.F.; Peters, J.A.; Lambert, J.J. The mechanism of action and pharmacological specificity of the anticonvulsant NMDA antagonist MK-801: A voltage clamp study on neuronal cells in culture. Br. J. Pharmacol., 1989, 96(2), 480-494. doi: 10.1111/j.1476-5381.1989.tb11841.x PMID: 2647206
- Övey, İ.S.; Nazıroğlu, M. Effects of homocysteine and memantine on oxidative stress related TRP cation channels in in-vitro model of Alzheimers disease. J. Recept. Signal Transduct. Res., 2021, 41(3), 273-283. doi: 10.1080/10799893.2020.1806321 PMID: 32781866
- Guo, H.; Camargo, L.M.; Yeboah, F.; Digan, M.E.; Niu, H.; Pan, Y.; Reiling, S.; Llavina, S.G.; Weihofen, W.A.; Wang, H.R.; Shanker, Y.G.; Stams, T.; Bill, A. A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine. Sci. Rep., 2017, 7(1), 11608. doi: 10.1038/s41598-017-11947-x PMID: 28912557
- Dingle, Y.T.L.; Liaudanskaya, V.; Finnegan, L.T.; Berlind, K.C.; Mizzoni, C.; Georgakoudi, I.; Nieland, T.J.F.; Kaplan, D.L. Functional characterization of three-dimensional cortical cultures for in vitro modeling of brain networks. iScience, 2020, 23(8), 101434. doi: 10.1016/j.isci.2020.101434 PMID: 32805649
- Lv, S.; Yao, K.; Zhang, Y.; Zhu, S. NMDA receptors as therapeutic targets for depression treatment: Evidence from clinical to basic research. Neuropharmacology, 2023, 225, 109378. doi: 10.1016/j.neuropharm.2022.109378 PMID: 36539011
- Zhou, Q.; Sheng, M. NMDA receptors in nervous system diseases. Neuropharmacology, 2013, 74, 69-75. doi: 10.1016/j.neuropharm.2013.03.030 PMID: 23583930
- Rodriguez, C.M.; Rodríguez, G.C.; Villalobos, C.; Núñez, L. Role of toll like receptor 4 in Alzheimers disease. Front. Immunol., 2020, 11, 1588. doi: 10.3389/fimmu.2020.01588 PMID: 32983082
- Özgün, A.; Marote, A.; Behie, L.A.; Salgado, A.; Garipcan, B. Extremely low frequency magnetic field induces human neuronal differentiation through NMDA receptor activation. J. Neural Transm., 2019, 126(10), 1281-1290. doi: 10.1007/s00702-019-02045-5 PMID: 31317262
- Groth, R.D.; Dunbar, R.L.; Mermelstein, P.G. Calcineurin regulation of neuronal plasticity. Biochem. Biophys. Res. Commun., 2003, 311(4), 1159-1171. doi: 10.1016/j.bbrc.2003.09.002 PMID: 14623302
- Bading, H. Nuclear calcium signalling in the regulation of brain function. Nat. Rev. Neurosci., 2013, 14(9), 593-608. doi: 10.1038/nrn3531 PMID: 23942469
- Matta, C.; Juhász, T.; Fodor, J.; Hajdú, T.; Katona, É.; Somogyi, S.C.; Takács, R.; Vágó, J.; Oláh, T.; Bartók, Á.; Varga, Z.; Panyi, G.; Csernoch, L.; Zákány, R. N-methyl-D-aspartate (NMDA) receptor expression and function is required for early chondrogenesis. Cell Commun. Signal., 2019, 17(1), 166. doi: 10.1186/s12964-019-0487-3 PMID: 31842918
- Garcia-Durillo, M.; Frenguelli, B.G. Antagonism of P2X7 receptors enhances lorazepam action in delaying seizure onset in an in vitro model of status epilepticus. Neuropharmacology, 2023, 239, 109647. doi: 10.1016/j.neuropharm.2023.109647 PMID: 37459909
- Companys-Alemany, J.; Turcu, A.L.; Bellver-Sanchis, A.; Loza, M.I.; Brea, J.M.; Canudas, A.M.; Leiva, R.; Vázquez, S.; Pallàs, M.; Ferré, G.C. A novel NMDA receptor antagonist protects against cognitive decline presented by senescent mice. Pharmaceutics, 2020, 12(3), 284. doi: 10.3390/pharmaceutics12030284 PMID: 32235699
- Gattuso, J.J.; Wilson, C.; Hannan, A.J.; Renoir, T. Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour. Neuropharmacology, 2023, 239, 109689. doi: 10.1016/j.neuropharm.2023.109689 PMID: 37597609
- 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(8), 1301-1317. doi: 10.1111/j.1476-5381.2009.00304.x PMID: 19594762
- Gregory, N.S.; Harris, A.L.; Robinson, C.R.; Dougherty, P.M.; Fuchs, P.N.; Sluka, K.A. An overview of animal models of pain: Disease models and outcome measures. J. Pain, 2013, 14(11), 1255-1269. doi: 10.1016/j.jpain.2013.06.008 PMID: 24035349
- Bouali-Benazzouz, R.; Landry, M.; Benazzouz, A.; Fossat, P. Neuropathic pain modeling: Focus on synaptic and ion channel mechanisms. Prog. Neurobiol., 2021, 201, 102030. doi: 10.1016/j.pneurobio.2021.102030 PMID: 33711402
- Thouaye, M.; Yalcin, I. Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons. Pharmacol. Ther., 2023, 251, 108546. doi: 10.1016/j.pharmthera.2023.108546 PMID: 37832728
- Huang, J.C.; Salt, T.E.; Voaden, M.J.; Marshall, J. Non- competitive NMDA-receptor antagonists and anoxic degeneration of the ERG B-wave in vitro. Eye, 1991, 5(4), 476-480. doi: 10.1038/eye.1991.77 PMID: 1660413
- Siu, A.; Drachtman, R. Dextromethorphan: A review of N-methyl-d-aspartate receptor antagonist in the management of pain. CNS Drug Rev., 2007, 13(1), 96-106. doi: 10.1111/j.1527-3458.2007.00006.x PMID: 17461892
- Nguyen, L.; Thomas, K.L.; Lucke-Wold, B.P.; Cavendish, J.Z.; Crowe, M.S.; Matsumoto, R.R. Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders. Pharmacol. Ther., 2016, 159, 1-22. doi: 10.1016/j.pharmthera.2016.01.016 PMID: 26826604
- Welch, L.; Sovner, R. The treatment of a chronic organic mental disorder with dextromethorphan in a man with severe mental retardation. Br. J. Psychiatry, 1992, 161(1), 118-120. doi: 10.1192/bjp.161.1.118 PMID: 1638308
- Woodard, C.; Groden, J.; Goodwin, M.; Shanower, C.; Bianco, J. The treatment of the behavioral sequelae of autism with dextromethorphan: A case report. J. Autism Dev. Disord., 2005, 35(4), 515-518. doi: 10.1007/s10803-005-5041-z PMID: 16134036
- Chez, M.; Kile, S.; Lepage, C.; Parise, C.; Benabides, B.; Hankins, A. A randomized, placebo-controlled, blinded, crossover, pilot study of the effects of dextromethorphan/quinidine for the treatment of neurobehavioral symptoms in adults with autism. J. Autism Dev. Disord., 2020, 50(5), 1532-1538. doi: 10.1007/s10803-018-3703-x PMID: 30109474
- Pioro, E.P. Review of dextromethorphan 20 mg/quinidine 10 mg (NUEDEXTA®) for pseudobulbar affect. Neurol. Ther., 2014, 3(1), 15-28. doi: 10.1007/s40120-014-0018-5 PMID: 26000221
- Mabunga, D.F.N.; Gonzales, E.L.T.; Kim, J.; Kim, K.C.; Shin, C.Y. Exploring the validity of valproic acid animal model of autism. Exp. Neurobiol., 2015, 24(4), 285-300. doi: 10.5607/en.2015.24.4.285 PMID: 26713077
- Long, X.Y.; Wang, S.; Luo, Z.W.; Zhang, X.; Xu, H. Comparison of three administration modes for establishing a zebrafish seizure model induced by N-Methyl-D-aspartic acid. World J. Psychiatry, 2020, 10(7), 150-161. doi: 10.5498/wjp.v10.i7.150 PMID: 32844092
- Lanznaster, D.; Dal-Cim, T.; Piermartiri, T.C.B.; Tasca, C.I. Guanosine: A neuromodulator with therapeutic potential in brain disorders. Aging Dis., 2016, 7(5), 657-679. doi: 10.14336/AD.2016.0208 PMID: 27699087
- Kapur, J. Role of NMDA receptors in the pathophysiology and treatment of status epilepticus. Epilepsia Open, 2018, 3(S2), 165-168. doi: 10.1002/epi4.12270 PMID: 30564775
- Elmorsy, S.A.; Soliman, G.F.; Rashed, L.A.; Elgendy, H. Dexmedetomidine and propofol sedation requirements in an autistic rat model. Korean J. Anesthesiol., 2019, 72(2), 169-177. doi: 10.4097/kja.d.18.00005 PMID: 29843508
- Bjørklund, G.; Meguid, N.A.; El-Bana, M.A.; Tinkov, A.A.; Saad, K.; Dadar, M.; Hemimi, M.; Skalny, A.V.; Hosnedlová, B.; Kizek, R.; Osredkar, J.; Urbina, M.A.; Fabjan, T.; El-Houfey, A.A.; Czaplińska, K.J.; Gątarek, P.; Chirumbolo, S. Oxidative stress in autism spectrum disorder. Mol. Neurobiol., 2020, 57(5), 2314-2332. doi: 10.1007/s12035-019-01742-2 PMID: 32026227
Supplementary files
