NMDA receptor antagonist#Uncompetitive channel blockers

NMDA receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia.{{cite journal | vauthors = Pender JW | title = Dissociative anesthesia | journal = JAMA | volume = 215 | issue = 7 | pages = 1126–30 | date = February 1971 | pmid = 5107596 | doi = 10.1001/jama.1971.03180200050011 | pmc = 1518731 }} Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics.{{cite journal | vauthors = Ceber M, Salihoglu T | title = Ketamine may be the first choice for anesthesia in burn patients | journal = Journal of Burn Care & Research | volume = 27 | issue = 5 | pages = 760–2 | year = 2006 | pmid = 16998413 | doi = 10.1097/01.BCR.0000238091.41737.7C }}{{cite journal | vauthors = Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A | title = Use of ketamine in severe status asthmaticus in intensive care unit | journal = Iranian Journal of Allergy, Asthma, and Immunology | volume = 2 | issue = 4 | pages = 175–80 | date = December 2003 | pmid = 17301376 }} Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world{{cite journal | vauthors = Equinozzi R, Robuschi M | title = Comparative efficacy and tolerability of pholcodine and dextromethorphan in the management of patients with acute, non-productive cough : a randomized, double-blind, multicenter study | journal = Treatments in Respiratory Medicine | volume = 5 | issue = 6 | pages = 509–13 | year = 2006 | pmid = 17154678 | doi = 10.2165/00151829-200605060-00014 | s2cid = 58323644 }}), is known to be an NMDA receptor antagonist.

Numerous detrimental symptoms are linked to depressed NMDA receptor function. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging.{{cite journal | vauthors = Newcomer JW, Krystal JH | title = NMDA receptor regulation of memory and behavior in humans | journal = Hippocampus | volume = 11 | issue = 5 | pages = 529–42 | year = 2001 | pmid = 11732706 | doi = 10.1002/hipo.1069 | s2cid = 32617915 }} Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia).{{cite journal | vauthors = Lipina T, Labrie V, Weiner I, Roder J | title = Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia | journal = Psychopharmacology | volume = 179 | issue = 1 | pages = 54–67 | date = April 2005 | pmid = 15759151 | doi = 10.1007/s00213-005-2210-x | s2cid = 10858756 }} Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis".{{cite journal | vauthors = Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G | title = The kynurenic acid hypothesis of schizophrenia | journal = Physiology & Behavior | volume = 92 | issue = 1–2 | pages = 203–9 | date = September 2007 | pmid = 17573079 | doi = 10.1016/j.physbeh.2007.05.025 | s2cid = 46156877 }} NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis. Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares,{{cite journal | vauthors = Muir KW, Lees KR | title = Clinical experience with excitatory amino acid antagonist drugs | journal = Stroke | volume = 26 | issue = 3 | pages = 503–13 | date = March 1995 | pmid = 7886734 | doi = 10.1161/01.STR.26.3.503 | url = http://stroke.ahajournals.org/cgi/content/full/26/3/503 | url-access = subscription }} catatonia,{{cite journal | vauthors = Aarts MM, Tymianski M | title = Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors | journal = Biochemical Pharmacology | volume = 66 | issue = 6 | pages = 877–86 | date = September 2003 | pmid = 12963474 | doi = 10.1016/S0006-2952(03)00297-1 }} ataxia,{{cite book |vauthors=Kim AH, Kerchner GA, Choi DW |chapter=Blocking Excitotoxicity |veditors=Marcoux FW, Choi DW |title=CNS Neuroprotection |publisher=Springer |location=New York |year=2002 |pages=3–36 }} anesthesia,{{cite journal | vauthors = Kristensen JD, Svensson B, Gordh T | title = The NMDA-receptor antagonist CPP abolishes neurogenic 'wind-up pain' after intrathecal administration in humans | journal = Pain | volume = 51 | issue = 2 | pages = 249–53 | date = November 1992 | pmid = 1484720 | doi = 10.1016/0304-3959(92)90266-E | s2cid = 37828325 }} and learning and memory deficits.{{cite journal | vauthors = Rockstroh S, Emre M, Tarral A, Pokorny R | title = Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans | journal = Psychopharmacology | volume = 124 | issue = 3 | pages = 261–6 | date = April 1996 | pmid = 8740048 | doi = 10.1007/BF02246666 | s2cid = 36727794 }}

Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug.{{cite journal | vauthors = Lim DK | title = Ketamine associated psychedelic effects and dependence | journal = Singapore Medical Journal | volume = 44 | issue = 1 | pages = 31–4 | date = January 2003 | pmid = 12762561 }}

Most NMDA receptor antagonists are metabolized in the liver.{{cite journal | vauthors = Chia YY, Liu K, Chow LH, Lee TY | title = The preoperative administration of intravenous dextromethorphan reduces postoperative morphine consumption | journal = Anesthesia and Analgesia | volume = 89 | issue = 3 | pages = 748–52 | date = September 1999 | pmid = 10475318 | doi = 10.1097/00000539-199909000-00041 | doi-access = free }}{{cite journal | vauthors = Kharasch ED, Labroo R | title = Metabolism of ketamine stereoisomers by human liver microsomes | journal = Anesthesiology | volume = 77 | issue = 6 | pages = 1201–7 | date = December 1992 | pmid = 1466470 | doi = 10.1097/00000542-199212000-00022 | doi-access = free }} Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.{{cite journal | vauthors = Livingston A, Waterman AE | title = The development of tolerance to ketamine in rats and the significance of hepatic metabolism | journal = British Journal of Pharmacology | volume = 64 | issue = 1 | pages = 63–9 | date = September 1978 | pmid = 698482 | pmc = 1668251 | doi = 10.1111/j.1476-5381.1978.tb08641.x }}

NMDA receptor antagonists are also under investigation as antidepressants. Ketamine has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019, esketamine, an NMDA antagonizing enantiomer of ketamine, was approved for use as an antidepressant in the United States.{{Cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm|title=FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic|website=Food and Drug Administration |date=24 March 2020}} In 2022, Auvelity was approved by the FDA for the treatment of depression.{{citation-needed|date=April 2023}} This combination medication contains dextromethorphan, an NMDA receptor antagonist.

{{Main|Olney's lesions}}

Olney's lesions involve mass vacuolization of neurons observed in rodents.{{cite journal | vauthors = Olney JW, Labruyere J, Price MT | title = Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs | journal = Science | volume = 244 | issue = 4910 | pages = 1360–2 | date = June 1989 | pmid = 2660263 | doi = 10.1126/science.2660263 | bibcode = 1989Sci...244.1360O }}{{cite book | vauthors = Hargreaves RJ, Hill RG, Iversen LL | chapter = Neuroprotective NMDA Antagonists: The Controversy over Their Potential for Adverse Effects on Cortical Neuronal Morphology | title = Brain Edema IX | journal = Acta Neurochirurgica. Supplementum | volume = 60 | pages = 15–9 | year = 1994 | pmid = 7976530 | doi = 10.1007/978-3-7091-9334-1_4 | isbn = 978-3-7091-9336-5 }} However, many suggest that this is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity.{{cite journal | vauthors = Sun L, Li Q, Li Q, Zhang Y, Liu D, Jiang H, Pan F, Yew DT | title = Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys | journal = Addiction Biology | volume = 19 | issue = 2 | pages = 185–94 | date = March 2014 | pmid = 23145560 | doi = 10.1111/adb.12004 | s2cid = 23028521 }}{{cite journal | vauthors = Slikker W, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C | title = Ketamine-induced neuronal cell death in the perinatal rhesus monkey | journal = Toxicological Sciences | volume = 98 | issue = 1 | pages = 145–58 | date = July 2007 | pmid = 17426105 | doi = 10.1093/toxsci/kfm084 | doi-access = free }} A 2009 review found no evidence of ketamine-induced neuron death in humans.{{cite journal | vauthors = Green SM, Coté CJ | title = Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine | journal = Annals of Emergency Medicine | volume = 54 | issue = 2 | pages = 181–90 | date = August 2009 | pmid = 18990467 | doi = 10.1016/j.annemergmed.2008.10.003 }} However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not.{{cite journal | vauthors = Morgan CJ, Muetzelfeldt L, Curran HV | title = Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study | journal = Addiction | volume = 105 | issue = 1 | pages = 121–33 | date = January 2010 | pmid = 19919593 | doi = 10.1111/j.1360-0443.2009.02761.x }}

Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates,{{cite journal | vauthors = Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA | title = NMDA antagonist neurotoxicity: mechanism and prevention | journal = Science | volume = 254 | issue = 5037 | pages = 1515–8 | date = December 1991 | pmid = 1835799 | doi = 10.1126/science.1835799 | bibcode = 1991Sci...254.1515O }} ethanol,{{cite journal | vauthors = Farber NB, Heinkel C, Dribben WH, Nemmers B, Jiang X | title = In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity | journal = Brain Research | volume = 1028 | issue = 1 | pages = 66–74 | date = November 2004 | pmid = 15518643 | doi = 10.1016/j.brainres.2004.08.065 | s2cid = 9346522 }} 5-HT_2A serotonin receptor agonists,{{cite journal | vauthors = Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW | title = Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity | journal = Neuropsychopharmacology | volume = 18 | issue = 1 | pages = 57–62 | date = January 1998 | pmid = 9408919 | doi = 10.1016/S0893-133X(97)00127-9 | doi-access = free }} anticonvulsants,{{cite journal | vauthors = Farber N, Jiang X, Heinkel C, Nemmers B | title = Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity | journal = Molecular Psychiatry | volume = 7 | issue = 1 | pages = 726–733 | date = 23 August 2002 | pmid = 12192617 | doi =10.1038/sj.mp.4001087 | doi-access = free }} and muscimol.{{cite journal | vauthors = Farber NB, Jiang X, Dikranian K, Nemmers B | title = Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions | journal = Brain Research | volume = 993 | issue = 1–2 | pages = 90–100 | date = December 2003 | pmid = 14642834 | doi = 10.1016/j.brainres.2003.09.002 | s2cid = 39247873 }}

Since NMDA receptor overactivation is implicated in excitotoxicity, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal, traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions,{{cite journal | vauthors = Maas AI | title = Neuroprotective agents in traumatic brain injury | journal = Expert Opinion on Investigational Drugs | volume = 10 | issue = 4 | pages = 753–67 | date = April 2001 | pmid = 11281824 | doi = 10.1517/13543784.10.4.753 | s2cid = 12111585 }} and studies have started to find agents that prevent this neurotoxicity. Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however.{{cite journal | vauthors = Chen HS, Lipton SA | title = The chemical biology of clinically tolerated NMDA receptor antagonists | journal = Journal of Neurochemistry | volume = 97 | issue = 6 | pages = 1611–26 | date = June 2006 | pmid = 16805772 | doi = 10.1111/j.1471-4159.2006.03991.x | doi-access = free }} Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal.{{cite journal | vauthors = Gardoni F, Di Luca M | title = New targets for pharmacological intervention in the glutamatergic synapse | journal = European Journal of Pharmacology | volume = 545 | issue = 1 | pages = 2–10 | date = September 2006 | pmid = 16831414 | doi = 10.1016/j.ejphar.2006.06.022 }}

Image:NMDA receptor activation and antagonists.PNG

The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."

Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists block binding to neurotransmitter glutamate sites; glycine antagonists block binding to glycine sites; noncompetitive antagonists inhibit binding to NMDARs allosteric sites; and uncompetitive antagonists block binding to a site within the ion channel.

• AP5 (APV, R-2-amino-5-phosphonopentanoate).{{cite journal | vauthors = Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschöp MH, Gao XB, Horvath TL | title = Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite | journal = The Journal of Clinical Investigation | volume = 116 | issue = 12 | pages = 3229–39 | date = December 2006 | pmid = 17060947 | pmc = 1618869 | doi = 10.1172/JCI29867 }}
• AP7 (2-amino-7-phosphonoheptanoic acid).{{cite journal | vauthors = van den Bos R, Charria Ortiz GA, Cools AR | title = Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure | journal = Behavioural Brain Research | volume = 48 | issue = 2 | pages = 165–70 | date = June 1992 | pmid = 1535501 | doi = 10.1016/S0166-4328(05)80153-6 | s2cid = 3997779 }}
• CGP-37849{{cite journal | vauthors = Fagg GE, Olpe HR, Pozza MF, Baud J, Steinmann M, Schmutz M, Portet C, Baumann P, Thedinga K, Bittiger H | display-authors = 6 | title = CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity | journal = British Journal of Pharmacology | volume = 99 | issue = 4 | pages = 791–7 | date = April 1990 | pmid = 1972895 | pmc = 1917531 | doi = 10.1111/j.1476-5381.1990.tb13008.x }}
• CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid).{{cite journal | vauthors = Eblen F, Löschmann PA, Wüllner U, Turski L, Klockgether T | title = Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions | journal = European Journal of Pharmacology | volume = 299 | issue = 1–3 | pages = 9–16 | date = March 1996 | pmid = 8901001 | doi = 10.1016/0014-2999(95)00795-4 }}
• Selfotel: an anxiolytic, anticonvulsant but with possible neurotoxic effects.

• 3-MeO-PCP: an analogue of PCP
• 8A-PDHQ: a high affinity PCP structural analogue.
• Amantadine: used for treating Parkinson's disease, influenza, and Alzheimer's disease.[http://www.clinicaltrials.gov/ct/show/NCT00188383?order=4 "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy"], University Health Network, Toronto, September 2005"MedlinePlus Drug Information: Amantadine." [https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682064.html MedlinePlus website] Accessed 29 May 2007
• Atomoxetine: a norepinephrine reuptake inhibitor used in the treatment of ADHD.{{cite journal | vauthors = Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Föhr KJ | title = Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations | journal = British Journal of Pharmacology | volume = 160 | issue = 2 | pages = 283–91 | date = May 2010 | pmid = 20423340 | pmc = 2874851 | doi = 10.1111/j.1476-5381.2010.00707.x }}
• AZD6765.
• Agmatine: Blocks NMDA receptors and other cation ligand-gated channels. Can also potentiate opioid analgesia.
• Argiotoxin: polyamine toxins produced by the orb-weaver spider (Araneus gemma and Argiope lobata)
• Chloroform: an early anesthetic.
• Cyclopropane: an early anesthetic.
• Delucemine: also an SSRI with neuroprotective properties.
• Desflurane: an inhalational anesthetic.
• Dextrallorphan: a more potent analogue of dextromethorphan.
• Dextromethorphan: an antitussive found in OTC cough medicines.{{cite journal | vauthors = Wong BY, Coulter DA, Choi DW, Prince DA | title = Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices | journal = Neuroscience Letters | volume = 85 | issue = 2 | pages = 261–6 | date = February 1988 | pmid = 2897648 | doi = 10.1016/0304-3940(88)90362-X | s2cid = 9903072 | doi-access = free }}
• Dextrorphan: active metabolite of dextromethorphan.
• Dextromethadone: (S)-enantiomer of the drug methadone that has low affinity for opioid receptors and exhibits rapid antidepressant effects in animal models.
• Diphenidine: a designer drug and PCP analogue sold on the internet.European Patent 0346791 1,2-Diarylethylamines for Treatment of Neurotoxic Injury.
• Dizocilpine (MK-801): an experimental drug used in scientific research.{{cite journal | vauthors = Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N, Wozniak DF, Olney JW | title = Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex | journal = Experimental Neurology | volume = 123 | issue = 2 | pages = 204–15 | date = October 1993 | pmid = 8405286 | doi = 10.1006/exnr.1993.1153 | s2cid = 24839154 }}
• Ethanol: also known as alcohol, a widely used intoxicant.
• Eticyclidine: a slightly more potent dissociative anesthetic than phencyclidine but with greater nausea/unpleasant taste, that was discontinued early in its development due to these digestive complaints.
• Gacyclidine: an experimental drug developed for neuroprotection and is being studied for the treatment of tinnitus.{{cite journal | last1=Maxwell | first1=Kenneth S. | last2=Robinson | first2=James M. | last3=Hoffmann | first3=Ines | last4=Hou | first4=Huiying J. | last5=Searchfield | first5=Grant | last6=Baguley | first6=David M. | last7=McMurry | first7=Gordon | last8=Piu | first8=Fabrice | last9=Anderson | first9=Jeffery J. | title=Intratympanic Administration of OTO-313 Reduces Tinnitus in Patients With Moderate to Severe, Persistent Tinnitus: A Phase 1/2 Study | journal=Otology & Neurotology | publisher=Ovid Technologies (Wolters Kluwer Health) | volume=42 | issue=10 | date=October 8, 2021 | issn=1531-7129 | doi=10.1097/mao.0000000000003369 | pages=e1625–e1633| pmid=34629442 | pmc=8584222 | doi-access=free }}
• Halothane: an inhalational anesthetic.
• Isoflurane: an inhalational anesthetic.
• Ketamine: a dissociative hallucinogen with antidepressant properties used as an anesthetic in humans and animals, a possible treatment in bipolar disorder patients with treatment-resistant depression, and used recreationally for its effects on the CNS.{{cite journal | vauthors = Harrison NL, Simmonds MA | title = Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex | journal = British Journal of Pharmacology | volume = 84 | issue = 2 | pages = 381–91 | date = February 1985 | pmid = 2858237 | pmc = 1987274 | doi = 10.1111/j.1476-5381.1985.tb12922.x }}
• Magnesium.
• Memantine: treatment for Alzheimer's disease.{{cite journal | vauthors = Chawla PS, Kochar MS | title = What's new in clinical pharmacology and therapeutics | journal = WMJ | volume = 105 | issue = 3 | pages = 24–9 | date = May 2006 | pmid = 16749321 }}
• Methoxetamine: a novel designer drug sold on the internet.{{Citation needed|date=September 2010}}
• Methoxydine: 4-MeO-PCP.
• Minocycline.{{cite journal | vauthors = Shultz RB, Zhong Y | title = Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury | journal = Neural Regeneration Research | volume = 12 | issue = 5 | pages = 702–713 | date = May 2017 | pmid = 28616020 | pmc = 5461601 | doi = 10.4103/1673-5374.206633 | doi-access = free }}
• Neramexane: a memantine analogue with nootropic, antidepressant properties. Also a nicotinic acetylcholine antagonist.
• Nitromemantine: a novel memantine derivative.{{cite journal | vauthors = Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Piña-Crespo JC, Lipton SA | title = Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 27 | pages = E2518–27 | date = July 2013 | pmid = 23776240 | pmc = 3704025 | doi = 10.1073/pnas.1306832110 | bibcode = 2013PNAS..110E2518T | doi-access = free }}
• Nitrous oxide: used for anesthesia, particularly in dentistry.{{cite journal | vauthors = Grasshoff C, Drexler B, Rudolph U, Antkowiak B | title = Anaesthetic drugs: linking molecular actions to clinical effects | journal = Current Pharmaceutical Design | volume = 12 | issue = 28 | pages = 3665–79 | year = 2006 | pmid = 17073666 | doi = 10.2174/138161206778522038 }}
• PD-137889: Potent NMDA receptor antagonist with roughly 30 times the potency of ketamine. Substitutes for PCP in animal studies.
• Phencyclidine: a dissociative anesthetic previously used in medicine, but its development was discontinued in the 1960s in favor of its successor ketamine due to its relatively high incidence of psychotomimetic effects. Abused recreational and legally controlled in most countries.
• Remacemide: a low affinity antagonist also a sodium-channel blocker.
• Rolicyclidine: a less potent analogue of phencyclidine, but seems to be seldom, if ever, abused.
• Sevoflurane: an inhalational anesthetic.
• Tenocyclidine: an analogue of phencyclidine that is more potent.
• Tiletamine: an animal anesthetic.{{cite journal | vauthors = Ko JC, Smith TA, Kuo WC, Nicklin CF | title = Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets | journal = Journal of the American Animal Hospital Association | volume = 34 | issue = 5 | pages = 407–16 | year = 1998 | pmid = 9728472 | doi = 10.5326/15473317-34-5-407 }}
• Eliprodil: an anticonvulsant drug with neuroprotective properties.
• Etoxadrol: a potent dissociative similar to PCP.
• Dexoxadrol: similar to etoxadrol.
• WMS-2539: potent fluorinated derivative of dexoxadrol.{{cite journal | vauthors = Banerjee A, Schepmann D, Köhler J, Würthwein EU, Wünsch B | title = Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists | journal = Bioorganic & Medicinal Chemistry | volume = 18 | issue = 22 | pages = 7855–67 | date = November 2010 | pmid = 20965735 | doi = 10.1016/j.bmc.2010.09.047 }}
• NEFA: a moderate affinity antagonist.

• Aptiganel (Cerestat, CNS-1102): binds the Mg²⁺ binding site within the channel of the NMDA receptor.
• HU-211: an enantiomer of the potent cannabinoid HU-210 which lacks cannabinoid effects and instead acts as a potent non-competitive NMDA antagonist.{{cite journal | vauthors = Nadler V, Mechoulam R, Sokolovsky M | title = The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain | journal = Neuroscience Letters | volume = 162 | issue = 1–2 | pages = 43–5 | date = November 1993 | pmid = 8121633 | doi = 10.1016/0304-3940(93)90555-Y | s2cid = 34955663 }}
• Huperzine A.{{cite journal | vauthors = Zhang JM, Hu GY | title = Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons | journal = Neuroscience | volume = 105 | issue = 3 | pages = 663–9 | date = 2001 | pmid = 11516831 | doi = 10.1016/s0306-4522(01)00206-8 | s2cid = 25801039 }}{{cite journal | vauthors = Qian ZM, Ke Y | title = Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease? | journal = Frontiers in Aging Neuroscience | volume = 6 | pages = 216 | date = 2014 | pmid = 25191267 | pmc = 4137276 | doi = 10.3389/fnagi.2014.00216 | doi-access = free }}{{cite journal | vauthors = Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP | title = [+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats | journal = Chemico-Biological Interactions | volume = 175 | issue = 1–3 | pages = 387–95 | date = September 2008 | pmid = 18588864 | doi = 10.1016/j.cbi.2008.05.023 | url = https://zenodo.org/record/1258822 }}
• Dipeptide D-Phe-L-Tyr.{{cite journal | vauthors = Karlov D, Barygin O, Dron M, Palyulin V, Grigoriev V, Fedorov M | title = Short peptide with an inhibitory activity on the NMDA/Gly-induced currents | journal = SAR and QSAR in Environmental Research | volume = 30 | issue = 9 | pages = 683–695 | date = 2019 | doi = 10.1080/1062936X.2019.1653965 | s2cid = 202879710 }} weakly inhibit NMDA/Gly-induced currents possibly by ifenprodil-like mechanism.
• Ibogaine: a naturally-occurring alkaloid found in plants of the family Apocynaceae. Has been used, albeit with limited evidence, to treat opioid and other addictions.{{cite journal | vauthors = Popik P, Layer RT, Skolnick P | title = The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 672–4 | date = May 1994 | pmid = 7531855 | doi = 10.1007/BF02245000 | s2cid = 8779011 | url = https://zenodo.org/record/1232548 }}{{cite journal | vauthors = Brown TK | title = Ibogaine in the treatment of substance dependence | journal = Current Drug Abuse Reviews | volume = 6 | issue = 1 | pages = 3–16 | date = March 2013 | pmid = 23627782 | doi = 10.2174/15672050113109990001 }}
• Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.{{cite journal | vauthors = Muir KW | title = Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 53–60 | date = February 2006 | pmid = 16359918 | doi = 10.1016/j.coph.2005.12.002 }}
• Rhynchophylline an alkaloid, found in Kratom and Rubiaceae.
• Gabapentin: a calcium α₂δ ligand that is commonly used in diabetic neuropathy.{{cite journal | vauthors = Hara K, Sata T | title = Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes | journal = Acta Anaesthesiologica Scandinavica | volume = 51 | issue = 1 | pages = 122–8 | date = January 2007 | pmid = 17073851 | doi = 10.1111/j.1399-6576.2006.01183.x | s2cid = 32385475 }}

These drugs act at the glycine binding site:

• Rapastinel (GLYX-13) (weak partial agonist; IA = ~20%).
• NRX-1074 (weak partial agonist).
• 7-Chlorokynurenic acid.{{cite journal | vauthors = Hartley DM, Monyer H, Colamarino SA, Choi DW | title = 7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture | journal = The European Journal of Neuroscience | volume = 2 | issue = 4 | pages = 291–295 | year = 1990 | pmid = 12106035 | doi = 10.1111/j.1460-9568.1990.tb00420.x | s2cid = 26088526 }}
• 4-Chlorokynurenine (AV-101) (prodrug for 7-chlorokynurenic acid).
• 5,7-Dichlorokynurenic acid.{{cite journal | vauthors = Frankiewicz T, Pilc A, Parsons CG | title = Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices | journal = Neuropharmacology | volume = 39 | issue = 4 | pages = 631–42 | date = February 2000 | pmid = 10728884 | doi = 10.1016/S0028-3908(99)00168-9 | s2cid = 16639516 }}
• Kynurenic acid (a naturally occurring antagonist).{{cite journal | vauthors = Khan MJ, Seidman MD, Quirk WS, Shivapuja BG | title = Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig | journal = European Archives of Oto-Rhino-Laryngology | volume = 257 | issue = 4 | pages = 177–81 | year = 2000 | pmid = 10867830 | doi = 10.1007/s004050050218 | s2cid = 21396821 }}
• TK-40 (competitive antagonist at the GluN1 glycine binding site).{{cite journal | vauthors = Kvist T, Steffensen TB, Greenwood JR, Mehrzad Tabrizi F, Hansen KB, Gajhede M, Pickering DS, Traynelis SF, Kastrup JS, Bräuner-Osborne H | title = Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site | journal = The Journal of Biological Chemistry | volume = 288 | issue = 46 | pages = 33124–35 | date = November 2013 | pmid = 24072709 | pmc = 3829161 | doi = 10.1074/jbc.M113.480210 | doi-access = free }}
• 1-Aminocyclopropanecarboxylic acid (ACPC).
• L-Phenylalanine.{{cite journal | vauthors = Glushakov AV, Dennis DM, Morey TE, Sumners C, Cucchiara RF, Seubert CN, Martynyuk AE | title = Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria | journal = Molecular Psychiatry | volume = 7 | issue = 4 | pages = 359–67 | year = 2002 | pmid = 11986979 | doi = 10.1038/sj.mp.4000976 | doi-access = free }} a naturally occurring amino acid (equilibrium dissociation constant (K_B) from Schild regression is 573 μM{{cite journal | vauthors = Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE | title = Long-term changes in glutamatergic synaptic transmission in phenylketonuria | journal = Brain | volume = 128 | issue = Pt 2 | pages = 300–7 | date = February 2005 | pmid = 15634735 | doi = 10.1093/brain/awh354 | doi-access = free }}).
• Xenon: an anesthetic.{{cite journal | vauthors = Banks P, Franks NP, Dickinson R | title = Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia | journal = Anesthesiology | volume = 112 | issue = 3 | pages = 614–22 | date = March 2010 | pmid = 20124979 | doi = 10.1097/ALN.0b013e3181cea398 | doi-access = free }}

{{see also|NMDA receptor modulator}}

• List of investigational antidepressants
• Discovery and development of memantine and related compounds

{{Reflist}}

{{Pharmacomodulation}}

{{Hallucinogens}}

{{Ionotropic glutamate receptor modulators}}

{{ADHD_pharmacotherapies}}

{{DEFAULTSORT:Nmda Receptor Antagonist}}

Category:Neurotrauma

Category:General anesthetics