Editing NMDA receptor (section)

==Ligands==

===Agonists===
[[Image:L-Glutaminsäure - L-Glutamic_acid.svg|thumb|right|200px|<small>L</small>-[[Glutamic acid]] (glutamate), the major endogenous agonist of the main site of the NMDAR]]
[[Image:Glycine-2D-skeletal.svg|thumb|right|150px|[[Glycine]], the major endogenous agonist of the glycine co-agonist site of the NMDAR]]

Activation of NMDA receptors requires binding of [[glutamic acid|glutamate]] or [[aspartic acid|aspartate]] (aspartate does not stimulate the receptors as strongly).<ref name="pmid15703381">{{cite journal | vauthors = Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ | display-authors = 6 | title = Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1470–1484 | date = May 2005 | pmid = 15703381 | doi = 10.1124/mol.104.008185 | s2cid = 13505187 }}</ref> In addition, NMDARs also require the binding of the [[co-agonist]] [[glycine]] for the efficient opening of the ion channel, which is a part of this receptor.

[[D-Serine|<small>D</small>-Serine]] has also been found to co-agonize the NMDA receptor with even greater potency than glycine.<ref name="pmid17033043">{{cite journal | vauthors = Wolosker H | title = D-serine regulation of NMDA receptor activity | journal = Science's STKE | volume = 2006 | issue = 356 | pages = pe41 | date = October 2006 | pmid = 17033043 | doi = 10.1126/stke.3562006pe41 | s2cid = 39125762 }}</ref> It is produced by [[serine racemase]], and is enriched in the same areas as NMDA receptors. Removal of <small>D</small>-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that <small>D</small>-serine can be released both by neurons and astrocytes to regulate NMDA receptors. Note that D-serine has also been shown to work as an antagonist / inverse co-agonist for ''t''-NMDA receptors.<ref name=":6">{{cite journal | vauthors = Beesley S, Kumar SS | title = The t-N-methyl-d-aspartate receptor: Making the case for d-Serine to be considered its inverse co-agonist | journal = Neuropharmacology | volume = 238 | pages = 109654 | date = November 2023 | pmid = 37437688 | doi = 10.1016/j.neuropharm.2023.109654 | doi-access = free }}</ref><ref name=":3" />

NMDA receptor (NMDAR)-mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast [[Mg ion (physiology)|Mg<sup>2+</sup>]] unbinding kinetics, increasing channel open probability with depolarization. This property is fundamental to the role of the NMDA receptor in [[memory]] and [[learning]], and it has been suggested that this channel is a biochemical substrate of [[Hebbian learning]], where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

====Examples====
Some known NMDA receptor agonists include:
* [[Amino acid]]s and amino acid derivatives
** [[Aspartic acid]] (aspartate) ([[aspartic acid|<small>D</small>-aspartic acid]], [[aspartic acid|<small>L</small>-aspartic acid]]) – endogenous glutamate site agonist. The word ''N''-methyl-<small>D</small>-aspartate (NMDA) is partially derived from <small>D</small>-aspartate.
** [[Glutamic acid]] (glutamate) – endogenous glutamate site agonist
*** [[Tetrazolylglycine]] – synthetic glutamate site agonist
*** [[Homocysteic acid]] – endogenous glutamate site agonist
*** [[Ibotenic acid]] – naturally occurring glutamate site agonist found in ''[[Amanita muscaria]]''
*** [[Quinolinic acid]] (quinolinate) – endogenous glutamate site agonist
** [[Glycine]] – endogenous glycine site agonist
*** [[Alanine]] ([[alanine|<small>D</small>-alanine]], [[alanine|<small>L</small>-alanine]]) – endogenous glycine site agonist
*** [[Milacemide]] – synthetic glycine site agonist; prodrug of [[glycine]]
*** [[Sarcosine]] (monomethylglycine) – endogenous glycine site agonist
*** [[Serine]] ([[serine|<small>D</small>-serine]], [[serine|<small>L</small>-serine]]) – endogenous glycine site agonist
* [[Positive allosteric modulator]]s
** [[Cerebrosterol]] – endogenous weak positive allosteric modulator
** [[Cholesterol]] – endogenous weak positive allosteric modulator
** [[Dehydroepiandrosterone]] (DHEA) – endogenous weak positive allosteric modulator
** [[Dehydroepiandrosterone sulfate]] (DHEA-S) – endogenous weak positive allosteric modulator
** [[Nebostinel]] (neboglamine) – synthetic positive allosteric modulator of the glycine site
** [[Pregnenolone sulfate]] – endogenous weak positive allosteric modulator
* Polyamines
** [[Spermidine]] – endogenous polyamine site agonist
** [[Spermine]] – endogenous polyamine site agonist

==== Neramexane ====
[[File:Neramexane.svg|thumb|right|'''Figure 6:''' Chemical structure of neramexane, second generation memantine derivative]]
An example of memantine derivative is [[neramexane]] which was discovered by studying number of aminoalkyl [[cyclohexanes]], with memantine as the template, as NMDA receptor antagonists. Neramexane binds to the same site as memantine within the NMDA receptor associated channel and with comparable affinity. It does also show very similar bioavailability and blocking kinetics [[in vivo]] as memantine. Neramexane went to [[clinical trials]] for four indications, including Alzheimer's disease.<ref name="Wanka" />

===Partial agonists===
[[Image:NMDA.svg|thumb|right|200px|[[N-Methyl-D-aspartic acid|''N''-Methyl-<small>D</small>-aspartic acid]] (NMDA), a synthetic partial agonist of the main site of the NMDAR]]

[[N-Methyl-D-aspartic acid|''N''-Methyl-<small>D</small>-aspartic acid]] (NMDA), which the NMDA receptor was named after, is a partial agonist of the active or glutamate recognition site.

3,5-Dibromo-<small>L</small>-phenylalanine, a naturally occurring halogenated derivative of [[Phenylalanine|<small>L</small>-phenylalanine]], is a weak partial NMDA receptor agonist acting on the glycine site.<ref>{{cite journal | vauthors = Yarotskyy V, Glushakov AV, Sumners C, Gravenstein N, Dennis DM, Seubert CN, Martynyuk AE | title = Differential modulation of glutamatergic transmission by 3,5-dibromo-L-phenylalanine | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1648–1654 | date = May 2005 | pmid = 15687225 | doi = 10.1124/mol.104.005983 | s2cid = 11672391 }}</ref><ref>{{Cite journal |last1=Kagiyama |first1=Tomoko |last2=Glushakov |first2=Alexander V. |last3=Sumners |first3=Colin |last4=Roose |first4=Brandy |last5=Dennis |first5=Donn M. |last6=Phillips |first6=M. Ian |last7=Ozcan |first7=Mehmet S. |last8=Seubert |first8=Christoph N. |last9=Martynyuk |first9=Anatoly E. |date=April 8, 2004 |title=Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine |url=https://www.ahajournals.org/doi/10.1161/01.str.0000125722.10606.07 |journal=Stroke |volume=35 |issue=5 |pages=1192–1196 |doi=10.1161/01.STR.0000125722.10606.07|pmid=15073406 |url-access=subscription }}</ref> 3,5-Dibromo-<small>L</small>-phenylalanine has been proposed a novel therapeutic drug candidate for treatment of neuropsychiatric disorders and diseases such as [[schizophrenia]],<ref>{{cite journal | vauthors = Martynyuk AE, Seubert CN, Yarotskyy V, Glushakov AV, Gravenstein N, Sumners C, Dennis DM | title = Halogenated derivatives of aromatic amino acids exhibit balanced antiglutamatergic actions: potential applications for the treatment of neurological and neuropsychiatric disorders | journal = Recent Patents on CNS Drug Discovery | volume = 1 | issue = 3 | pages = 261–270 | date = November 2006 | pmid = 18221208 | doi = 10.2174/157488906778773706 }}</ref> and neurological disorders such as [[ischemic stroke]] and [[epileptic seizure]]s.<ref>{{cite journal | vauthors = Cao W, Shah HP, Glushakov AV, Mecca AP, Shi P, Sumners C, Seubert CN, Martynyuk AE | display-authors = 6 | title = Efficacy of 3,5-dibromo-L-phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit | journal = British Journal of Pharmacology | volume = 158 | issue = 8 | pages = 2005–2013 | date = December 2009 | pmid = 20050189 | pmc = 2807662 | doi = 10.1111/j.1476-5381.2009.00498.x }}</ref>

Other partial agonists of the NMDA receptor acting on novel sites such as [[rapastinel]] (GLYX-13) and [[apimostinel]] (NRX-1074) are now viewed for the development of new drugs with antidepressant and analgesic effects without obvious psychotomimetic activities.<ref>J. Moskal, D. Leander, R. Burch (2010). Unlocking the Therapeutic Potential of the NMDA Receptor. [http://www.dddmag.com/articles/2010/10/unlocking-therapeutic-potential-nmda-receptor ''Drug Discovery & Development News''.] Retrieved 19 December 2013.</ref>

====Examples====
* [[Aminocyclopropanecarboxylic acid]] (ACC) – synthetic glycine site partial agonist
* [[Cycloserine]] ([[D-cycloserine|<small>D</small>-cycloserine]]) – naturally occurring glycine site partial agonist found in ''[[Streptomyces|Streptomyces orchidaceus]]''
* [[HA-966]] and [[L-687,414]] – synthetic glycine site weak partial agonists
* [[Homoquinolinic acid]] – synthetic glutamate site partial agonist
* [[N-Methyl-D-aspartic acid|''N''-Methyl-<small>D</small>-aspartic acid]] (NMDA) – synthetic glutamate site partial agonist

Positive allosteric modulators include:
* [[AGN-241751|Zelquistinel]] (GATE-251) – synthetic novel site partial agonist
* [[Apimostinel]] (GATE-202) – synthetic novel site partial agonist
* [[Rapastinel]] (GLYX-13) – synthetic novel site partial agonist<ref>{{cite journal | vauthors = Donello JE, Banerjee P, Li YX, Guo YX, Yoshitake T, Zhang XL, Miry O, Kehr J, Stanton PK, Gross AL, Burgdorf JS, Kroes RA, Moskal JR | display-authors = 6 | title = Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects | journal = The International Journal of Neuropsychopharmacology | volume = 22 | issue = 3 | pages = 247–259 | date = March 2019 | pmid = 30544218 | pmc = 6403082 | doi = 10.1093/ijnp/pyy101 }}</ref>

===Antagonists===
{{Main|NMDA receptor antagonist}}
[[Image:Ketamine.svg|thumb|right|150px|[[Ketamine]], a synthetic general anesthetic and one of the best-known NMDAR antagonists]]

Antagonists of the NMDA receptor are used as [[anesthetic]]s for animals and sometimes humans, and are often used as [[recreational drug]]s due to their [[hallucinogenic]] properties, in addition to their unique effects at elevated dosages such as [[dissociation (psychology)|dissociation]]. When certain NMDA receptor antagonists are given to rodents in large doses, they can cause a form of [[brain damage]] called [[Olney's lesions]]. NMDA receptor antagonists that have been shown to induce Olney's lesions include [[ketamine]], [[phencyclidine]], and [[dextrorphan]] (a metabolite of [[dextromethorphan]]), as well as some NMDA receptor antagonists used only in research environments. So far, the published research on Olney's lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists.<ref name="urlErowid DXM Vaults">{{cite web | url = http://www.erowid.org/chemicals/dxm/dxm_health2.shtml | title = The Bad News Isn't In: A Look at Dissociative-Induced Brain Damage and Cognitive Impairment | vauthors = Anderson C | date = 2003-06-01 | work = Erowid DXM Vaults : Health | access-date = 2008-12-17}}</ref>

Most NMDAR antagonists are [[uncompetitive antagonist|uncompetitive]] or [[noncompetitive antagonist|noncompetitive blocker]]s of the channel pore or are antagonists of the glycine co-regulatory site rather than antagonists of the active/glutamate site.

====Examples====
Common agents in which NMDA receptor antagonism is the primary or a major mechanism of action:
* [[4-Chlorokynurenine]] (AV-101) – glycine site antagonist; prodrug of [[7-chlorokynurenic acid]]<ref name="Flight2013">{{cite journal | vauthors = Flight MH | title = Trial watch: phase II boost for glutamate-targeted antidepressants | journal = Nature Reviews. Drug Discovery | volume = 12 | issue = 12 | pages = 897 | date = December 2013 | pmid = 24287771 | doi = 10.1038/nrd4178 | s2cid = 33113283 | doi-access = free }}</ref><ref name="VécseiSzalárdy2012">{{cite journal | vauthors = Vécsei L, Szalárdy L, Fülöp F, Toldi J | title = Kynurenines in the CNS: recent advances and new questions | journal = Nature Reviews. Drug Discovery | volume = 12 | issue = 1 | pages = 64–82 | date = January 2013 | pmid = 23237916 | doi = 10.1038/nrd3793 | s2cid = 31914015 }}</ref>
* [[7-Chlorokynurenic acid]] – glycine site antagonist
* [[Agmatine]] – endogenous polyamine site antagonist<ref name="pmid10785653">{{cite journal | vauthors = Reis DJ, Regunathan S | title = Is agmatine a novel neurotransmitter in brain? | journal = Trends in Pharmacological Sciences | volume = 21 | issue = 5 | pages = 187–193 | date = May 2000 | pmid = 10785653 | doi = 10.1016/s0165-6147(00)01460-7 | doi-access = free }}</ref><ref name="pmid12363406">{{cite journal | vauthors = Gibson DA, Harris BR, Rogers DT, Littleton JM | title = Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil | journal = Brain Research | volume = 952 | issue = 1 | pages = 71–77 | date = October 2002 | pmid = 12363406 | doi = 10.1016/s0006-8993(02)03198-0 | s2cid = 38065910 }}</ref>
* Argiotoxin-636 – naturally occurring dizocilpine or related site antagonist found in ''[[Argiope (spider)|Argiope]]'' venom
* [[AP5]] – glutamate site antagonist
* [[AP-7 (drug)|AP7]] – glutamate site antagonist
* [[CGP-37849]] – glutamate site antagonist
* [[Serine|D-serine]] - ''t''-NMDA receptor antagonist / inverse co-agonist<ref name=":6" /><ref name=":3" />
* [[Delucemine]] (NPS-1506) – dizocilpine or related site antagonist; derived from argiotoxin-636<ref name="pmid11026487">{{cite journal | vauthors = Mueller AL, Artman LD, Balandrin MF, Brady E, Chien Y, DelMar EG, Kierstead A, Marriott TB, Moe ST, Raszkiewicz JL, VanWagenen B, Wells D | display-authors = 6 | title = NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience | journal = Amino Acids | volume = 19 | issue = 1 | pages = 177–179 | year = 2000 | pmid = 11026487 | doi = 10.1007/s007260070047 | s2cid = 2899648 }}</ref><ref name="pmid26257776">{{cite journal | vauthors = Monge-Fuentes V, Gomes FM, Campos GA, Silva J, Biolchi AM, Dos Anjos LC, Gonçalves JC, Lopes KS, Mortari MR | display-authors = 6 | title = Neuroactive compounds obtained from arthropod venoms as new therapeutic platforms for the treatment of neurological disorders | journal = The Journal of Venomous Animals and Toxins Including Tropical Diseases | volume = 21 | pages = 31 | year = 2015 | pmid = 26257776 | pmc = 4529710 | doi = 10.1186/s40409-015-0031-x | doi-access = free }}</ref>
* [[Dextromethorphan]] (DXM) – dizocilpine site antagonist; prodrug of [[dextrorphan]]
* [[Dextrorphan]] (DXO) – dizocilpine site antagonist
* [[Dexanabinol]] – dizocilpine-related site antagonist<ref name="ShohamiMechoulam2000">{{cite journal | vauthors = Pop E | title = Nonpsychotropic synthetic cannabinoids | journal = Current Pharmaceutical Design | volume = 6 | issue = 13 | pages = 1347–1360 | date = September 2000 | pmid = 10903397 | doi = 10.2174/1381612003399446 }}</ref><ref name="pmid2556719">{{cite journal | vauthors = Feigenbaum JJ, Bergmann F, Richmond SA, Mechoulam R, Nadler V, Kloog Y, Sokolovsky M | title = Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 23 | pages = 9584–9587 | date = December 1989 | pmid = 2556719 | pmc = 298542 | doi = 10.1073/pnas.86.23.9584 | doi-access = free | bibcode = 1989PNAS...86.9584F }}</ref><ref name="pmid8242387">{{cite journal | vauthors = Nadler V, Mechoulam R, Sokolovsky M | title = Blockade of 45Ca2+ influx through the N-methyl-D-aspartate receptor ion channel by the non-psychoactive cannabinoid HU-211 | journal = Brain Research | volume = 622 | issue = 1–2 | pages = 79–85 | date = September 1993 | pmid = 8242387 | doi = 10.1016/0006-8993(93)90804-v | s2cid = 36689761 }}</ref>
* [[Diethyl ether]] – unknown site antagonist
* [[Diphenidine]] – dizocilpine site antagonist
* [[Dizocilpine]] (MK-801) – dizocilpine site antagonist
* [[Eliprodil]] – ifenprodil site antagonist
* [[Esketamine]] – dizocilpine site antagonist
* [[Hodgkinsine]] – undefined site antagonist
* [[Ifenprodil]] – ifenprodil site antagonist<ref name="pmid21677647">{{cite journal | vauthors = Karakas E, Simorowski N, Furukawa H | title = Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors | journal = Nature | volume = 475 | issue = 7355 | pages = 249–253 | date = June 2011 | pmid = 21677647 | pmc = 3171209 | doi = 10.1038/nature10180 }}</ref>
* [[Kaitocephalin]] – naturally occurring glutamate site antagonist found in ''[[Eupenicillium shearii]]''
* [[Ketamine]] – dizocilpine site antagonist
* [[Kynurenic acid]] – endogenous glycine site antagonist
* [[Lanicemine]] – low-trapping dizocilpine site antagonist
* [[LY-235959]] – glutamate site antagonist
* [[Memantine]] – low-trapping dizocilpine site antagonist
* [[Methoxetamine]] – dizocilpine site antagonist
* [[Midafotel]] – glutamate site antagonist
* [[Nitrous oxide]] (N<sub>2</sub>O) – undefined site antagonist
* [[PEAQX]] – glutamate site antagonist
* [[Perzinfotel]] – glutamate site antagonist
* [[Phencyclidine]] (PCP) – dizocilpine site antagonist
* [[Phenylalanine]] - a naturally occurring amino acid, glycine site antagonist<ref name=pmid11986979>{{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 = 359–367 | year = 2002 | pmid = 11986979 | doi = 10.1038/sj.mp.4000976 | doi-access = free }}</ref><ref>{{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 | display-authors = 6 | title = Long-term changes in glutamatergic synaptic transmission in phenylketonuria | journal = Brain | volume = 128 | issue = Pt 2 | pages = 300–307 | date = February 2005 | pmid = 15634735 | doi = 10.1093/brain/awh354 | doi-access = free }}</ref>
* [[Psychotridine]] – undefined site antagonist
* [[Selfotel]] – glutamate site antagonist
* [[Tiletamine]] – dizocilpine site antagonist
* [[Traxoprodil]] – ifenprodil site antagonist
* [[Xenon]] – unknown site antagonist

Some common agents in which weak NMDA receptor antagonism is a secondary or additional action include:
* [[Amantadine]] – an [[antiviral]] and [[Management of Parkinson's disease#Medication|antiparkinsonian]] drug; low-trapping dizocilpine site antagonist<ref>{{ClinicalTrialsGov|NCT00188383|Effects of ''N''-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy}}</ref>
* [[Atomoxetine]] – a [[norepinephrine reuptake inhibitor]] used to treat {{abbrlink|ADHD|attention-deficit hyperactivity disorder}}<ref name="Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations">{{cite journal | vauthors = Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, Fegert JM, Boeckers TM, Föhr KJ | display-authors = 6 | title = Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations | journal = British Journal of Pharmacology | volume = 160 | issue = 2 | pages = 283–291 | date = May 2010 | pmid = 20423340 | pmc = 2874851 | doi = 10.1111/j.1476-5381.2010.00707.x }}</ref>
* [[Dextropropoxyphene]] – an [[opioid analgesic]]
* [[Ethanol]] ([[alcoholic drink|alcohol]]) – a [[euphoriant]], [[sedative]], and [[anxiolytic]] used recreationally; unknown site antagonist
* [[Guaifenesin]] – an [[expectorant]]
* [[Huperzine A]] – a naturally occurring [[acetylcholinesterase inhibitor]] and potential [[antidementia]] agent
* [[Ibogaine]] – a naturally occurring [[hallucinogen]] and [[antiaddictive]] agent
* [[Ketobemidone]] – an opioid analgesic
* [[Methadone]] – an opioid analgesic
* [[Minocycline]] – an [[antibiotic]]<ref name="pmid28616020">{{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 }}</ref>
* [[Tramadol]] – an atypical opioid analgesic and [[serotonin releasing agent]]

==== Nitromemantine ====
The NMDA receptor is regulated via [[nitrosylation]] and aminoadamantane can be used as a target-directed shuttle to bring nitrogen oxide (NO) close to the site within the NMDA receptor where it can nitrosylate and regulate the ion channel conductivity.<ref name="Wanka" /> A NO donor that can be used to decrease NMDA receptor activity is the alkyl nitrate nitroglycerin. Unlike many other NO donors, alkyl nitrates do not have potential NO associated [[neurotoxic]] effects. Alkyl nitrates donate NO in the form of a nitro group as seen in figure 7, -NO<sub>2</sub>-, which is a safe donor that avoids neurotoxicity. The nitro group must be targeted to the NMDA receptor, otherwise other effects of NO such as dilatation of blood vessels and consequent [[hypotension]] could result.<ref name="Lipton3" />
[[Nitromemantine]] is a second-generation derivative of memantine, it reduces excitotoxicity mediated by overactivation of the glutamatergic system by blocking NMDA receptor without sacrificing safety. Provisional studies in animal models show that nitromemantines are more effective than memantine as neuroprotectants, both [[in vitro]] and in vivo. Memantine and newer derivatives could become very important weapons in the fight against neuronal damage.<ref name="Lipton1" />
[[File:Nitromemantine.jpg|thumb|center|450px|'''Figure 7:''' Nitroglycerin donate ONO<sub>2</sub> group that leads to second generation memantine analog, [[nitromemantine]]]]

[[Negative allosteric modulator]]s include:
* [[25-Hydroxycholesterol]] – endogenous weak negative allosteric modulator
* [[Conantokin]]s – naturally occurring negative allosteric modulators of the polyamine site found in ''[[Conus geographus]]''<ref name="pmid1328523">{{cite journal | vauthors = Skolnick P, Boje K, Miller R, Pennington M, Maccecchini ML | title = Noncompetitive inhibition of N-methyl-D-aspartate by conantokin-G: evidence for an allosteric interaction at polyamine sites | journal = Journal of Neurochemistry | volume = 59 | issue = 4 | pages = 1516–1521 | date = October 1992 | pmid = 1328523 | doi = 10.1111/j.1471-4159.1992.tb08468.x | s2cid = 25871948 }}</ref>

===Modulators===

====Examples====
The NMDA receptor is modulated by a number of [[endogenous]] and [[exogenous]] compounds:<ref name="pmid15670959">{{cite journal | vauthors = Huggins DJ, Grant GH | title = The function of the amino terminal domain in NMDA receptor modulation | journal = Journal of Molecular Graphics & Modelling | volume = 23 | issue = 4 | pages = 381–388 | date = January 2005 | pmid = 15670959 | doi = 10.1016/j.jmgm.2004.11.006 | bibcode = 2005JMGM...23..381H }}</ref>
* [[Aminoglycoside]]s have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.
* [[CDK5]] regulates the amount of [[NR2B]]-containing NMDA receptors on the synaptic membrane, thus affecting [[synaptic plasticity]].<ref name="pmid17529984">{{cite journal | vauthors = Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA | display-authors = 6 | title = Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation | journal = Nature Neuroscience | volume = 10 | issue = 7 | pages = 880–886 | date = July 2007 | pmid = 17529984 | pmc = 3910113 | doi = 10.1038/nn1914 }}</ref><ref name="pmid18184784">{{cite journal | vauthors = Zhang S, Edelmann L, Liu J, Crandall JE, Morabito MA | title = Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors | journal = The Journal of Neuroscience | volume = 28 | issue = 2 | pages = 415–424 | date = January 2008 | pmid = 18184784 | pmc = 6670547 | doi = 10.1523/JNEUROSCI.1900-07.2008 }}</ref>
* [[Polyamine]]s do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.
* [[Reelin]] modulates NMDA function through [[Src Family Kinases|Src family kinases]] and [[DAB1]].<ref name="pmid16148228">{{cite journal | vauthors = Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J | title = Reelin modulates NMDA receptor activity in cortical neurons | journal = The Journal of Neuroscience | volume = 25 | issue = 36 | pages = 8209–8216 | date = September 2005 | pmid = 16148228 | pmc = 6725528 | doi = 10.1523/JNEUROSCI.1951-05.2005 }}</ref> significantly enhancing [[Long-term potentiation|LTP]] in the [[hippocampus]].
* [[Src (gene)|Src]] kinase enhances NMDA receptor currents.<ref name="pmid9005855">{{cite journal | vauthors = Yu XM, Askalan R, Keil GJ, Salter MW | title = NMDA channel regulation by channel-associated protein tyrosine kinase Src | journal = Science | volume = 275 | issue = 5300 | pages = 674–678 | date = January 1997 | pmid = 9005855 | doi = 10.1126/science.275.5300.674 | s2cid = 39275755 }}</ref>
* [[Sodium|Na<sup>+</sup>]], [[K ion (physiology)|K<sup>+</sup>]] and [[Ca ion (physiology)|Ca<sup>2+</sup>]] not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.<ref>{{cite journal | vauthors = Petrozziello T, Boscia F, Tedeschi V, Pannaccione A, de Rosa V, Corvino A, Severino B, Annunziato L, Secondo A | display-authors = 6 | title = Na<sup>+</sup>/Ca<sup>2+</sup> exchanger isoform 1 takes part to the Ca<sup>2+</sup>-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-L-alanine | journal = Cell Communication and Signaling | volume = 20 | issue = 1 | pages = 8 | date = January 2022 | pmid = 35022040 | pmc = 8756626 | doi = 10.1186/s12964-021-00813-z | doi-access = free }}</ref>
* [[Zinc#Biological role|Zn<sup>2+</sup>]] and [[Copper|Cu<sup>2+</sup>]] generally block NMDA current activity in a noncompetitive and a voltage-independent manner. However zinc may potentiate or inhibit the current depending on the neural activity.<ref>{{cite journal | vauthors = Horning MS, Trombley PQ | title = Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms | journal = Journal of Neurophysiology | volume = 86 | issue = 4 | pages = 1652–1660 | date = October 2001 | pmid = 11600628 | doi = 10.1152/jn.2001.86.4.1652 | s2cid = 6141092 }}</ref>
* [[Lead|Pb]]<sup>2+</sup><ref>{{cite journal | vauthors = Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR | title = Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling | journal = Toxicological Sciences | volume = 116 | issue = 1 | pages = 249–263 | date = July 2010 | pmid = 20375082 | pmc = 2886862 | doi = 10.1093/toxsci/kfq111 }}</ref> is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb<sup>2+</sup> exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.
* Proteins of the [[major histocompatibility complex]] class I are endogenous negative regulators of NMDAR-mediated currents in the adult hippocampus,<ref name="pmid21135233">{{cite journal | vauthors = Fourgeaud L, Davenport CM, Tyler CM, Cheng TT, Spencer MB, Boulanger LM | title = MHC class I modulates NMDA receptor function and AMPA receptor trafficking | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 51 | pages = 22278–22283 | date = December 2010 | pmid = 21135233 | pmc = 3009822 | doi = 10.1073/pnas.0914064107 | doi-access = free | bibcode = 2010PNAS..10722278F }}</ref> and are required for appropriate NMDAR-induced changes in [[AMPAR]] trafficking <ref name="pmid21135233"/> and NMDAR-dependent [[synaptic plasticity]] and [[learning]] and [[memory]].<ref name="pmid11118151">{{cite journal | vauthors = Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ | title = Functional requirement for class I MHC in CNS development and plasticity | journal = Science | volume = 290 | issue = 5499 | pages = 2155–2159 | date = December 2000 | pmid = 11118151 | pmc = 2175035 | doi = 10.1126/science.290.5499.2155 | bibcode = 2000Sci...290.2155H }}</ref><ref>{{cite journal | vauthors = Nelson PA, Sage JR, Wood SC, Davenport CM, Anagnostaras SG, Boulanger LM | title = MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression | journal = Learning & Memory | volume = 20 | issue = 9 | pages = 505–517 | date = September 2013 | pmid = 23959708 | pmc = 3744042 | doi = 10.1101/lm.031351.113 }}</ref>
* The activity of NMDA receptors is also strikingly sensitive to the changes in [[pH]], and partially inhibited by the ambient concentration of H<sup>+</sup> under physiological conditions.<ref>{{cite journal | vauthors = Traynelis SF, Cull-Candy SG | title = Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons | journal = Nature | volume = 345 | issue = 6273 | pages = 347–350 | date = May 1990 | pmid = 1692970 | doi = 10.1038/345347a0 | s2cid = 4351139 | bibcode = 1990Natur.345..347T }}</ref> The level of inhibition by H<sup>+</sup> is greatly reduced in receptors containing the NR1a subtype, which contains the positively charged insert Exon 5. The effect of this insert may be mimicked by positively charged polyamines and aminoglycosides, explaining their mode of action.
* NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site."<ref name="pmid2696504">{{cite journal | vauthors = Aizenman E, Lipton SA, Loring RH | title = Selective modulation of NMDA responses by reduction and oxidation | journal = Neuron | volume = 2 | issue = 3 | pages = 1257–1263 | date = March 1989 | pmid = 2696504 | doi = 10.1016/0896-6273(89)90310-3 | s2cid = 10324716 }}</ref> Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as [[glutathione]], [[lipoic acid]], and the essential nutrient [[pyrroloquinoline quinone]].<ref>{{Cite journal |last1=Aizenman |first1=Elias |last2=Loring |first2=Ralph H. |last3=Reynolds |first3=Ian J. |last4=Rosenberg |first4=Paul A. |date=July 24, 2020 |title=The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc |journal=Frontiers in Neuroscience |volume=14 |pages=778 |doi=10.3389/fnins.2020.00778 |doi-access=free |issn=1662-4548 |pmc=7393236 |pmid=32792905}}</ref>

=== Development of NMDA receptor antagonists ===
The main problem with the development of NMDA antagonists for neuroprotection is that physiological NMDA receptor activity is essential for normal neuronal function. Complete blockade of all NMDA receptor activity results in side effects such as [[hallucinations]], agitation and [[anesthesia]]. To be clinically relevant, an NMDA receptor antagonist must limit its action to blockade of excessive activation, without limiting normal function of the receptor.<ref name="Lipton2" />

==== Competitive NMDA receptor antagonists ====
[[Competitive]] NMDA receptor antagonists, which were developed first, are not a good option because they compete and bind to the same site (NR2 subunit) on the receptor as the agonist, glutamate, and therefore block normal function also.<ref name="Lipton2" /><ref name="Monaghan">{{cite book| vauthors = Monaghan DT, Jane DE | veditors = Van Dongen AM |title=Biology of the NMDA Receptor|date=2009|publisher=CRC Press|location=Boca Raton, Florida|isbn=978-1-4200-4414-0|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK5282/|chapter=Pharmacology of NMDA Receptors| series = Frontiers in Neuroscience |pmid=21204415}}</ref> They will block healthy areas of the brain prior to having an impact on pathological areas, because healthy areas contain lower levels of [[agonist]] than pathological areas. These antagonists can be displaced from the receptor by high concentration of glutamate which can exist under excitotoxic circumstances.<ref name="Chen" />

==== Noncompetitive NMDA receptor antagonists ====
[[File:NMDA receptor antagonist.jpg|thumb|right|200px|'''Figure 4:''' The chemical structures of MK-801, phencyclidine and ketamine, high affinity uncompetitive NMDA receptor antagonists]]
Uncompetitive NMDA receptor antagonists block within the ion channel at the Mg<sup>2+</sup> site (pore region) and prevent excessive influx of Ca<sup>2+</sup>. Noncompetitive antagonism refers to a type of block that an increased concentration of glutamate cannot overcome, and is dependent upon prior activation of the receptor by the agonist, i.e. it only enters the channel when it is opened by agonist.<ref name="Lipton2" /><ref name="Sonkusare">{{cite journal | vauthors = Sonkusare SK, Kaul CL, Ramarao P | title = Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope | journal = Pharmacological Research | volume = 51 | issue = 1 | pages = 1–17 | date = January 2005 | pmid = 15519530 | doi = 10.1016/j.phrs.2004.05.005 }}</ref>

==== Memantine and related compounds ====
[[File:Memantine and amantadine.jpg|thumb|right|300px|'''Figure 5:''' Chemical structures of memantine (right) and amantadine (left)]]
Because of these adverse side effects of high affinity blockers, the search for clinically successful NMDA receptor antagonists for neurodegenerative diseases continued and focused on developing low affinity blockers. However the affinity could not be too low and dwell time not too short (as seen with Mg<sup>2+</sup>) where membrane depolarization relieves the block. The discovery was thereby development of uncompetitive antagonist with longer dwell time than Mg<sup>2+</sup> in the channel but shorter than MK-801. That way the drug obtained would only block excessively open NMDA receptor associated channels but not normal neurotransmission.<ref name="Lipton2" /><ref name="Sonkusare" /> Memantine is that drug. It is a derivative of amantadine which was first an anti-influenza agent but was later discovered by coincidence to have efficacy in Parkinson's disease. Chemical structures of memantine and amantadine can be seen in figure 5. The compound was first thought to be [[dopaminergic]] or [[anticholinergic]] but was later found to be an NMDA receptor antagonist.<ref name="Dominguez" /><ref name="Lipton2" />

Memantine is the first drug approved for treatment of severe and more advanced [[Alzheimer's disease]], which for example anticholinergic drugs do not do much good for.<ref name="Sonkusare" /> It helps recovery of synaptic function and in that way improves impaired memory and learning.<ref name="Koch" /> In 2015 memantine is also in trials for therapeutic importance in additional neurological disorders.<ref name="Lipton3">{{cite journal | vauthors = Lipton SA | title = Pathologically activated therapeutics for neuroprotection | journal = Nature Reviews. Neuroscience | volume = 8 | issue = 10 | pages = 803–808 | date = October 2007 | pmid = 17882256 | doi = 10.1038/nrn2229 | s2cid = 34931289 }}</ref>

Many second-generation memantine derivatives have been in development that may show even better neuroprotective effects, where the main thought is to use other safe but effective modulatory sites on the NMDA receptor in addition to its associated ion channel.<ref name="Lipton3" />

=== Structure activity relationship (SAR) ===
[[File:SAR of amantadine and related compunds.jpg|thumb|right|300px|'''Figure 8:''' Structure activity relationship (SAR) of amantadine and related compounds]]

Memantine (1-amino-3,5-dimethyladamantane) is an aminoalkyl cyclohexane derivative and an atypical drug compound with non-planar, three dimensional tricyclic structure. Figure 8 shows SAR for aminoalkyl cyclohexane derivative. Memantine has several important features in its structure for its effectiveness:
* Three-ring structure with a bridgehead amine, -NH<sub>2</sub>
* The -NH<sub>2</sub> group is protonated under physiological pH of the body to carry a positive charge, -NH<sup>3+</sup>
* Two methyl (CH<sub>3</sub>) side groups which serve to prolong the dwell time and increase stability as well as affinity for the NMDA receptor channel compared with amantadine (1-adamantanamine).<ref name="Lipton1" /><ref name="Sonkusare" />

Despite the small structural difference between memantine and amantadine, two adamantane derivatives, the affinity for the binding site of NR1/NR2B subunit is much greater for memantine. In [[patch-clamp]] measurements memantine has an [[IC50|IC<sub>50</sub>]] of (2.3+0.3) μM while amantadine has an IC<sub>50</sub> of (71.0+11.1) μM.<ref name="Wanka" />
The binding site with the highest affinity is called the dominant binding site. It involves a connection between the amine group of memantine and the NR1-N161 binding pocket of the NR1/NR2B subunit. The methyl side groups play an important role in increasing the affinity to the open NMDA receptor channels and making it a much better neuroprotective drug than amantadine. The binding pockets for the methyl groups are considered to be at the NR1-A645 and NR2B-A644 of the NR1/NR2B.<ref name="Limapichat" /> The binding pockets are shown in figure 2.
Memantine binds at or near to the Mg<sup>2+</sup> site inside the NMDA receptor associated channel. The  -NH<sub>2</sub> group on memantine, which is protonated under physiological pH of the body, represents the region that binds at or near to the Mg<sup>2+</sup> site.<ref name="Lipton1" /> Adding two methyl groups to the -N on the memantine structure has shown to decrease affinity, giving an IC<sub>50</sub> value of (28.4+1.4) μM.<ref name="Wanka" />

==== Second generation derivative of memantine; nitromemantine ====
Several derivatives of Nitromemantine, a second-generation derivative of memantine, have been synthesized in order to perform a detailed [[structure activity relationship]] (SAR) of these novel drugs. One class, containing a nitro (NO<sub>2</sub>) group opposite to the bridgehead amine (NH<sub>2</sub>), showed a promising outcome. Nitromemantine utilizes memantine binding site on the NMDA receptor to target the NO<sub>x</sub> (X= 1 or 2) group for interaction with the S- nitrosylation/redox site external to the memantine binding site. Lengthening the side chains of memantine compensates for the worse drug affinity in the channel associated with the addition of the –ONO<sub>2</sub> group<ref name="Takahashi">{{cite journal | vauthors = Takahashi H, Xia P, Cui J, Talantova M, Bodhinathan K, Li W, Saleem S, Holland EA, Tong G, Piña-Crespo J, Zhang D, Nakanishi N, Larrick JW, McKercher SR, Nakamura T, Wang Y, Lipton SA | display-authors = 6 | title = Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease | journal = Scientific Reports | volume = 5 | pages = 14781 | date = October 2015 | pmid = 26477507 | pmc = 4609936 | doi = 10.1038/srep14781 | bibcode = 2015NatSR...514781T }}</ref>

=== Therapeutic application ===
Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and [[amyotrophic lateral sclerosis]].<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /><ref name="Koch" /> Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.<ref name="Chen" /><ref name="Kemp" /><ref name="Lipton1" /> It is, however, important to preserve physiological NMDA receptor activity while trying to block its excessive, excitotoxic activity. This can possibly be achieved by uncompetitive antagonists, blocking the receptor's ion channel when excessively open <ref name="Lipton1" />

Memantine is an example of uncompetitive NMDA receptor antagonist that has approved indication for the neurodegenerative disease Alzheimer's disease. In 2015 memantine is still in clinical trials for additional neurological diseases.<ref name="Limapichat" /><ref name="Lipton3" />