NMDA receptor - wikipedia NMDA receptor `` NR1 '' redirects here. For the submarine, see NR - 1. Stylized depiction of an activated NMDAR. Glutamate is in the glutamate - binding site and glycine is in the glycine - binding site. The allosteric site, which modulates receptor function when bound to a ligand, is not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine. The N - methyl - D - aspartate receptor ( also known as the NMDA receptor or NMDAR ), is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three types of ionotropic glutamate receptors, the others being the AMPA and kainate receptors. It is activated when glutamate and glycine ( or D - serine ) bind to it, and when activated it allows positively charged ions to flow through the cell membrane. The NMDA receptor is very important for controlling synaptic plasticity and memory function. The NMDAR is a specific type of ionotropic glutamate receptor. The NMDA receptor is so named because the agonist molecule N - methyl - D - aspartate ( NMDA ) binds selectively to it, and not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations, with a combined reversal potential near 0 mV. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage dependent. Extracellular magnesium ( Mg ) and zinc ( Zn ) ions can bind to specific sites on the receptor, blocking the passage of other cations through the open ion channel. Depolarization of the cell dislodges and repels the Mg and Zn ions from the pore, thus allowing a voltage - dependent flow of sodium ( Na ) and small amounts of calcium ( Ca ) ions into the cell and potassium ( K ) out of the cell. Ca flux through NMDARs is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory. The opening and closing ( gating ) of the NMDA receptor is complex. While it is primarily a ligand - gated channel, it does display weaker voltage - dependence modulation of the ligand - dependent gating. The ligand gating requires co-activation by two ligands : glutamate and either D - serine or glycine. The voltage - dependence of current through the channel is mainly due to binding of Mg or Zn ions to the protein as described above. The activity of the NMDA receptor is affected by many psychoactive drugs such as phencyclidine ( PCP ), alcohol ( ethanol ) and dextromethorphan ( DXM ). The anaesthetic and analgesic effects of the drugs ketamine and nitrous oxide are partially because of their effects on NMDA receptor activity. Contents 1 History 2 NMDA receptor 3 Mechanism of action 4 Variants 4.1 GluN1 4.2 GluN2 4.3 NR2B to NR2A switch 4.4 NR2B to NR2C switch 5 Role in excitotoxicity 5.1 Differing cascade pathways 5.2 Neural plasticity 5.3 Role of differing subunits 5.4 Excitotoxicity in a clinical setting 6 Ligands 6.1 Agonists 6.1. 1 Examples 6.1. 2 Neramexane 6.2 Partial agonists 6.2. 1 Examples 6.3 Antagonists 6.3. 1 Examples 6.3. 2 Nitromemantine 6.4 Modulators 6.4. 1 Examples 6.5 Development of NMDA receptor antagonist 6.5. 1 Competitive NMDA receptor antagonists 6.5. 2 Uncompetitive NMDA receptor antagonists 6.5. 3 Memantine and related compounds 6.6 Structure activity relationship ( SAR ) 6.6. 1 Second generation derivative of memantine ; Nitromemantine 6.7 Therapeutic application 7 Receptor modulation 8 Clinical significance 9 See also 10 References 11 External links In 1972 a possible therapeutic importance of memantine, an adamantane derivative, was discovered for treating neurodegenerative disorders. Since 1989 memantine has been recognized to be an uncompetitive antagonist of the N - methyl - D - aspartate receptor ( NMDA receptor ), entering the channel of the receptor after it has been activated and thereby blocking the flow of ions. The NMDA receptor channels play an important role in synaptic plasticity and synapse formation underlying memory, learning and formation of neural networks during development in the central nervous system ( CNS ). Overactivation of the receptor, causing excessive influx of Ca can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. The main problem with the development of NMDA receptor antagonist for neuroprotection is that the physiological NMDA receptor activity is essential for normal neuronal function. To be clinically accepted the antagonists must block excessive activation without blocking the normal function. History The discovery of NMDA receptors was followed by the synthesis and study of N - Methyl - D - aspartic acid ( NMDA ) in the 1960s by Jeff Watkins and colleagues. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways. Receptor subunit selectivity was discovered in the early 1990s, which led to recognition of a new class of compounds that selectively inhibit the NR2B subunit. These findings led to vigorous campaign in the pharmaceutical industry. From this it was considered that NMDA receptors were associated with a variety of neurological disorders such as epilepsy, Parkinson  ́ s, Alzheimer  ́ s, Huntington  ́ s and other CNS disorders. A fortuitous finding was made in 1968 when a woman was taking amantadine as flu medicine and experienced remarkable remission of her Parkinson 's symptoms. This finding, reported by Scawab et al., was the beginning of medicinal chemistry of adamantane derivatives in the context of diseases affecting the CNS. Before this finding, memantine, another adamantane derivative, had been synthesized by Eli Lilly and Company in 1963. The purpose was to develop hypoglycemic drug, but it showed no such efficacy. It was not until 1972 that a possible therapeutic importance of memantine for treating neurodegenerative disorders was discovered. From 1989 memantine has been recognized to be an uncompetitive antagonist of the NMDA receptor. NMDA receptor Figure 1 : NR1 / NR2B subunit Figure 2 : Transmembrane region of NR1 ( left ) and NR2B ( right ) subunits of NMDA receptor. The NMDA receptor is a glutamate and ion channel protein receptor that is activated when glycine and glutamate bind to it. The receptor is a heteromeric complex that interacts with multiple intracellular proteins by three different subunits : NR1, NR2 and NR3. NR1 has eight different subunits generated by alternative splicing from a single gene. There are four different NR2 subunits ( A-D ) and late in the 20 century NR3A and NR3B subunits have been reported. Six separate genes encode for NR2 and NR3. All the subunits share a common membrane topology that is dominated by a large extracellular N - terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C - terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins. Figure 1 shows a basic structure of NR1 / NR2 subunits that forms the binding site for memantine, Mg, MK - 801, ketamine and amantadine. Mg block the NMDA receptor channels in voltage dependent manner but they are highly permeable to Ca. Activation of the receptor depends on glutamate binding, D - serine or glycine binding at its NR1 - linked binding site and AMPA receptor - mediated depolarization of the postsynaptic membrane, which relieves the voltage - dependent channel block by Mg. Activation and opening of the receptors channel thus allows the flow of K, Na and Ca ions, and the influx of Ca triggers intracellular signaling pathways. Allosteric receptor binding sites for zinc, proteins and the polyamines spermidine and spermine are also modulators for the NMDA receptor channels. The NR2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangement. The basic structure and functions associated with the NMDA receptor can be attributed to the NR2B subunit. For example, the glutamate binding site and the control of the Mg block are formed by the NR2B subunit. The high affinity sites for glycine antagonist are also exclusively displayed by the NR1 / NR2B receptor. NR1 / NR2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists, but the transmembrane segments structures are not fully known as stated above. It is claimed that three binding sites within the receptor, A644 on the NR2B subunit and A645 and N616 on the NR1 subunit, are important for binding of memantine and related compounds as seen in figure 2. The NMDA receptor forms a heterotetramer between two GluN1 and two GluN2 subunits ( the subunits were previously denoted as NR1 and NR2 ), two obligatory NR1 subunits and two regionally localized NR2 subunits. A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits. Each receptor subunit has modular design and each structural module also represents a functional unit : The extracellular domain contains two globular structures : a modulatory domain and a ligand - binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. The agonist - binding module links to a membrane domain, which consists of three transmembrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels. The membrane domain contributes residues to the channel pore and is responsible for the receptor 's high - unitary conductance, high - calcium permeability, and voltage - dependent magnesium block. Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins. The glycine - binding modules of the NR1 and NR3 subunits and the glutamate - binding module of the NR2A subunit have been expressed as soluble proteins, and their three - dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid - binding bacterial proteins and with the glutamate - binding module of AMPA - receptors and kainate - receptors. Mechanism of action Overactivation of NMDA receptors, relieving the Mg block and causing excessive influx of Ca can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer 's disease, Parkinson 's disease and Huntington 's disease. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. 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 receptors ion channel when excessively open. Uncompetitive NMDA receptor antagonists, or channel blockers, enter the channel of the NMDA receptor after it has been activated and thereby block the flow of ions. MK - 801, ketamine, amantadine and memantine are examples of such antagonists, see figure 1. The off - rate of an antagonist from the receptors channel is an important factor as too slow off - rate can interfere with normal function of the receptor and too fast off - rate may give ineffective blockade of an excessively open receptor. Memantine is an example of an uncompetitive channel blocker of the NMDA receptor, with a relatively rapid off - rate and low affinity. At physiological pH its amine group is positively charged and its block of the channel is voltage - dependent. It thereby mimics the physiological function of Mg as channel blocker. Memantine only blocks NMDA receptor associated channels during prolonged activation of the receptor, as it occurs under excitotoxic conditions, by replacing magnesium at the binding site. During normal receptor activity the channels only stay open for several milliseconds and under those circumstances memantine is unable to bind within the channels and therefore does n't interfere with normal synaptic activity. Variants GluN1 There are eight variants of the NR1 subunit produced by alternative splicing of GRIN1 : NR1 - 1a, NR1 - 1b ; NR1 - 1a is the most abundantly expressed form. NR1 - 2a, NR1 - 2b ; NR1 - 3a, NR1 - 3b ; NR1 - 4a, NR1 - 4b ; GluN2 NR2 subunit in vertebrates ( left ) and invertebrates ( right ). Ryan et al., 2008 While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2 subunit are expressed in vertebrates and are referred to with the nomenclature NR2A through NR2D ( encoded by GRIN2A, GRIN2B, GRIN2C, GRIN2D ). Strong evidence shows that the genes encoding the NR2 subunits in vertebrates have undergone at least two rounds of gene duplication. They contain the binding - site for the neurotransmitter glutamate. More importantly, each NR2 subunit has a different intracellular C - terminal domain that can interact with different sets of signalling molecules. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding - site for the selective inhibitor ifenprodil. NR2B to NR2A switch The time course of NR2B - NR2A switch in human cerebellum. Bar - Shira et al., 2015 Whereas NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called the NR2B - NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor. For instance, greater ratios of the NR2B subunit leads to NMDA receptors which remain open longer compared to those with more NR2A. This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically altered ' doogie mice '. The detailed time course of this switch in the human cerebellum has been estimated using expression microarray and RNA seq and is shown in the figure on the right. There are three hypothetical models to describe this switch mechanism : Increase in synaptic NR2A along with decrease in NR2B Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A Increase of NR2A diluting the number of NR2B without the decrease of the latter. The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death. The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity. Disruption of the gene for NR2B in mice causes perinatal lethality, whereas the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity. One study suggests that reelin may play a role in the NMDA receptor maturation by increasing the NR2B subunit mobility. NR2B to NR2C switch Granule cell precursors ( GCPs ) of the cerebellum, after undergoing symmetric cell division in the external granule - cell layer ( EGL ), migrate into the internal granule - cell layer ( IGL ) where they downregulate NR2B and activate NR2C, a process that is independent of neuregulin beta signaling through ErbB2 and ErbB4 receptors. Role in excitotoxicity NMDA receptors have been implicated by a number of studies to be strongly involved with excitotoxicity. Because NMDA receptors play an important role in the health and function of neurons, there has been much discussion on how these receptors can affect both cell survival and cell death. Recent evidence supports the hypothesis that overstimulation of extrasynaptic NMDA receptors has more to do with excitotoxicity than stimulation of their synaptic counterparts. In addition, while stimulation of extrasynaptic NMDA receptors appear to contribute to cell death, there is evidence to suggest that stimulation of synaptic NMDA receptors contributes to the health and longevity of the cell. There is ample evidence to support the dual nature of NMDA receptors based on location, and the hypothesis explaining the two differing mechanisms is known as the `` localization hypothesis ''. Differing cascade pathways In order to support the localization hypothesis, it would be necessary to show differing cellular signaling pathways are activated by NMDA receptors based on its location within the cell membrane. Experiments have been designed to stimulate either synaptic or non-synaptic NMDA receptors exclusively. These types of experiments have shown that different pathways are being activated or regulated depending on the location of the signal origin. Many of these pathways use the same protein signals, but are regulated oppositely by NMDARs depending on its location. For example, synaptic NMDA excitation caused a decrease in the intracellular concentration of p38 mitogen - activated protein kinase ( p38MAPK ). Extrasynaptic stimulation NMDARs regulated p38MAPK in the opposite fashion, causing an increase in intracellular concentration. Experiments of this type have since been repeated with the results indicating these differences stretch across many pathways linked to cell survival and excitotoxicity. Two specific proteins have been identified as a major pathway responsible for these different cellular responses ERK1 / 2, and Jacob. ERK1 / 2 is responsible for phosphorylation of Jacob when excited by synaptic NMDARs. This information is then transported to the nucleus. Phosphorylation of Jacob does not take place with extrasynaptic NMDA stimulation. This allows the transcription factors in the nucleus to respond differently based in the phosphorylation state of Jacob. Neural plasticity NMDA receptors are also associated with synaptic plasticity. The idea that both synaptic and extrasynaptic NMDA receptors can affect long - term potentiation ( LTP ) and long - term depression ( LTD ) differently has also been explored. Experimental data suggest that extrasynaptic NMDA receptors inhibit LTP while producing LTD. Inhibition of LTP can be prevented with the introduction of a NMDA antagonist. A theta burst stimulation that usually induces LTP with synaptic NMDARs, when applied selectively to extrasynaptic NMDARs produces a LTD. Experimentation also indicates that extrasynaptic activity is not required for the formation of LTP. In addition, both synaptic and extrasynaptic are involved in expressing a full LTD. Role of differing subunits Another factor that seems to affect NMDAR induced toxicity is the observed variation in subunit makeup. NMDA receptors are heterotetramers with two GluN1 subunits and two variable subunits. Two of these variable subunits, GluN2A and GluN2B, have been shown to preferentially lead to cell survival and cell death cascades respectively. Although both subunits are found in synaptic and extrasynaptic NMDARs there is some evidence to suggest that the GluN2B subunit occurs more frequently in extrasynaptic receptors. This observation could help explain the dualistic role that NMDA receptors play in excitotoxicity. Despite the compelling evidence and the relative simplicity of these two theories working in tandem, there is still disagreement about the significance of these claims. Some problems in proving these theories arise with the difficulty of using pharmacological means to determine the subtypes of specific NMDARs. In addition, the theory of subunit variation does not explain how this effect might predominate, as it is widely held that the most common tetramer, made from two GluN1 subunits and one of each subunit GluN2A and GluN2B, makes up a high percentage of the NMDARs. Excitotoxicity in a clinical setting Excitotoxicity has been thought to play a role in the degenerative properties of neurodegenerative conditions since the late 1950s. NMDA receptors seem to play an important role in many of these degenerative diseases affecting the brain. Most notably excitotoxic events involving NMDA receptors have been linked to Alzheimer 's disease and Huntington 's disease as well as with other medical conditions such as strokes and epilepsy. Treating these conditions with one of the many known NMDA receptor antagonists, however, lead to a variety of unwanted side effects, some of which can be quite severe. These side effects are, in part, observed because the NMDA receptors do not just signal for cell death but also play an important role in its vitality. Treatment for these conditions might be found in blocking NDMA receptors not found at the synapse. Ligands Agonists Glutamic acid ( glutamate ), the major endogenous agonist of the main site of the NMDAR. Glycine, the major endogenous agonist of the glycine co-agonist site of the NMDAR. Activation of NMDA receptors requires binding of glutamate or aspartate ( aspartate does not stimulate the receptors as strongly ). 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 has also been found to co-agonize the NMDA receptor with even greater potency than glycine. It is produced by serine racemase, and is enriched in the same areas as NMDA receptors. Removal of D - serine can block NMDA - mediated excitatory neurotransmission in many areas. Recently, it has been shown that D - serine can be released both by neurons and astrocytes to regulate NMDA receptors. NMDA receptor ( NMDAR ) - mediated currents are directly related to membrane depolarization. NMDA agonists therefore exhibit fast Mg 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 : Alanine ( D - alanine, L - alanine ) -- endogenous glycine site agonist Aspartic acid ( asparatate ) -- endogenous glutamate site agonist Glutamic acid ( glutamate ) -- endogenous glutamate site agonist Glycine -- endogenous glycine site agonist Homocysteic acid -- endogenous glutamate site agonist Ibotenic acid -- naturally occurring glutamate site agonist found in Amanita muscaria Milacemide -- synthetic glycine site agonist ; prodrug of glycine Quinolinic acid ( quinolinate ) -- endogenous glutamate site agonist Sarcosine -- endogenous glycine site agonist Serine ( D - serine, L - serine ) -- endogenous glycine site agonist Spermidine -- endogenous polyamine site agonist Spermine -- endogenous polyamine site agonist Tetrazolylglycine -- synthetic glutamate site agonist Positive allosteric modulators include : 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 Neramexane 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, which can be seen in figure 6, 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. Partial agonists N - Methyl - D - aspartic acid ( NMDA ), a synthetic partial agonist of the main site of the NMDAR. N - Methyl - D - aspartic acid ( NMDA ), which the NMDA receptor was named after, is a partial agonist of the active or glutamate recognition site. Weak partial agonists of the glycine site of the NMDA receptor 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. Examples Aminocyclopropanecarboxylic acid ( ACC ) -- synthetic glycine site partial agonist Cycloserine ( D - cycloserine ) -- naturally occurring glycine site partial agonist found in Streptomyces orchidaceus HA - 966 -- synthetic glycine site weak partial agonist Homoquinolinic acid -- synthetic glutamate site partial agonist N - Methyl - D - aspartic acid ( NMDA ) -- synthetic glutamate site partial agonist Positive allosteric modulators include : Apimostinel ( NRX - 1074 ) -- synthetic weak partial agonist of an allosteric site of the glycine site Rapastinel ( GLYX - 13 ) -- synthetic weak partial agonist of an allosteric site of the glycine site Antagonists Main article : NMDA receptor antagonist Ketamine, a synthetic general anesthetic and one of the best - known NMDAR antagonists. Antagonists of the NMDA receptor are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs due to their hallucinogenic properties, in addition to their unique effects at elevated dosages such as 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. Most NMDAR antagonists are uncompetitive or noncompetitive blockers 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 7 - Chlorokynurenic acid -- glycine site antagonist Agmatine -- endogenous polyamine site antagonist Argiotoxin - 636 -- naturally occurring dizocilpine or related site antagonist found in Argiope venom AP5 -- glutamate site antagonist AP7 -- glutamate site antagonist CGP - 37849 -- glutamate site antagonist Delucemine ( NPS - 1506 ) -- dizocilpine or related site antagonist ; derived from argiotoxin - 636 Dextromethorphan ( DXM ) -- dizocilpine site antagonist ; prodrug of dextrorphan Dextrorphan ( DXO ) -- dizocilpine site antagonist Dexanabinol -- dizocilpine - related site antagonist 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 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 O ) -- undefined site antagonist PEAQX -- glutamate site antagonist Perzinfotel -- glutamate site antagonist Phencyclidine ( PCP ) -- dizocilpine site antagonist 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 antiparkinsonian drug ; low - trapping dizocilpine site antagonist Atomoxetine -- a stimulant used to treat ADHD Dextropropoxyphene -- an opioid analgesic Ethanol ( 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 Tramadol -- an atypical opioid analgesic 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. 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 -, 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. 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. Figure 7 : Nitroglycerin donate ONO group that leads to second generation memantine analog, nitromemantine. Negative allosteric modulators include : 25 - Hydroxycholesterol -- endogenous weak negative allosteric modulator Conantokins -- naturally occurring negative allosteric modulators of the polyamine site found in Conus geographus Modulators Examples The NMDA receptor is modulated by a number of endogenous and exogenous compounds : Aminoglycosides 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. Polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate - mediated responses. Reelin modulates NMDA function through Src family kinases and DAB1. significantly enhancing LTP in the hippocampus. Src kinase enhances NMDA receptor currents. Na, K and Ca not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. Zn and Cu 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. Pb is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb 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, and are required for appropriate NMDAR - induced changes in AMPAR trafficking and NMDAR - dependent synaptic plasticity and learning and memory. The activity of NMDA receptors is also strikingly sensitive to the changes in pH, and partially inhibited by the ambient concentration of H under physiological conditions. The level of inhibition by H 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. '' 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. Development of NMDA receptor antagonist The main problem with the development of NMDA antagonist for neuroprotection is that the physiological NMDA receptor activity is essential for normal neuronal function. Complete blocking of all NMDA receptor activity therefore results in adverse side effects such as hallucination, agitation and anesthesia. To be clinically accepted the NMDA receptor antagonist must block excessive activation without blocking the normal function. Figure 3 shows simplified models of various types of NMDA receptor antagonists, which will be discussed further. 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. 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. Uncompetitive NMDA receptor antagonists Figure 4 : The chemical structures of MK - 801, phencyclidine and ketamine, high affinity uncompetitive NMDA receptor antagonists. Uncompetitive NMDA receptor antagonists however block within the ion channel at the Mg site ( pore region ) and in that way prevent excessive influx of Ca. Uncompetitive block refers to a type of block that increased concentration of glutamate can not 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. The Mg block itself is too transient and flickery and therefore does n't block excessive Ca influx to the extent necessary to prevent neurological toxicity. High affinity antagonists for the Mg site are on the other hand good excitotoxicity blockers, such as MK - 801. They block open ion channels but the problem is when the ion channels close they get trapped inside resulting in undesirable side effects because of blocking normal as well as excessive activity. MK - 801 can not be given to humans because of that long dwell time in the channels and its blocking causes drowsiness and even coma. It 's therefore considered to be clinically unacceptable. Phencyclidine, which has slightly shorter dwell time but still too excessive, causes hallucination and is therefore not a good agent either for neurodegenerative diseases. Ketamine is another example of drug with slightly shorter dwell time but still excessive and it is used as anesthetic. Chemical structures of MK - 801, Phencyclidine and Ketamine can be seen in figure 4. Memantine and related compounds 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 ) where membrane depolarization relieves the block. The discovery was thereby development of uncompetitive antagonist with longer dwell time than Mg 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. 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. 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. It helps recovery of synaptic function and in that way improves impaired memory and learning. In 2015 memantine is also in trials for therapeutic importance in additional neurological disorders. 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. Structure activity relationship ( SAR ) 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 The - NH group is protonated under physiological pH of the body to carry a positive charge, - NH Two methyl ( CH ) 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 ). 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 IC of ( 2.3 + 0.3 ) μM while amantadine has an IC of ( 71.0 + 11.1 ) μM. 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. The binding pockets are shown in figure 2. Memantine binds at or near to the Mg site inside the NMDA receptor associated channel. The - NH group on memantine, which is protonated under physiological pH of the body, represents the region that binds at or near to the Mg site. Adding two methyl groups to the - N on the memantine structure has shown to decrease affinity, giving an IC value of ( 28.4 + 1.4 ) μM. 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 ) group opposite to the bridgehead amine ( NH ), showed a promising outcome. Nitromemantine utilizes memantine binding site on the NMDA receptor to target the NO ( 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 group 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. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. 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 receptors ion channel when excessively open 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. Receptor modulation The NMDA receptor is a non-specific cation channel that can allow the passage of Ca and Na into the cell and K out of the cell. The excitatory postsynaptic potential ( EPSP ) produced by activation of an NMDA receptor increases the concentration of Ca in the cell. The Ca can in turn function as a second messenger in various signaling pathways. However, the NMDA receptor cation channel is blocked by Mg at resting membrane potential. Magnesium unblock is not instantaneous, to unblock all available channels, the postsynaptic cell must be depolarized for a sufficiently long period of time ( in the scale of milliseconds ). Therefore, the NMDA receptor functions as a `` molecular coincidence detector ''. Its ion channel opens only when the following two conditions are met : glutamate is bound to the receptor, and the postsynaptic cell is depolarized ( which removes the Mg blocking the channel ). This property of the NMDA receptor explains many aspects of long - term potentiation ( LTP ) and synaptic plasticity. NMDA receptors are modulated by a number of endogenous and exogenous compounds and play a key role in a wide range of physiological ( e.g., memory ) and pathological processes ( e.g., excitotoxicity ). Clinical significance NMDAR antagonists like ketamine, esketamine, tiletamine, phencyclidine, nitrous oxide, and xenon are used as general anesthetics. These and similar drugs like dextromethorphan and methoxetamine also produce dissociative, hallucinogenic, and euphoriant effects and are used as recreational drugs. NMDAR inhibitors, including ketamine, esketamine ( JNJ - 54135419 ), rapastinel ( GLYX - 13 ), apimostinel ( NRX - 1074 ), 4 - chlorokynurenine ( AV - 101 ), and rislenemdaz ( CERC - 301, MK - 0657 ), are under development for the treatment of mood disorders, including major depressive disorder and treatment - resistant depression. In addition, ketamine is already employed for this purpose as an off - label therapy in some clinics. Memantine, a low - trapping NMDAR antagonist, is approved in the United States and Europe for the treatment of moderate - to - severe Alzheimer 's disease, and has now received a limited recommendation by the UK 's National Institute for Health and Care Excellence for patients who fail other treatment options. Cochlear NMDARs are the target of intense research to find pharmacological solutions to treat tinnitus. NMDARs are associated with a rare autoimmune disease, anti-NMDA receptor encephalitis, that usually occurs due to cross-reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in teratoma. These are known as anti-glutamate receptor antibodies. Compared to dopaminergic stimulants like methamphetamine, the NMDAR antagonist phencyclidine can produce a wider range of symptoms that resemble schizophrenia in healthy volunteers, in what has led to the glutamate hypothesis of schizophrenia. Experiments in which rodents are treated with NMDA receptor antagonist are today the most common model when it comes to testing of novel schizophrenia therapies or exploring the exact mechanism of drugs already approved for treatment of schizophrenia. NMDAR antagonists, for instance eliprodil, gavestinel, licostinel, and selfotel have been extensively investigated for the treatment of excitotoxicity - mediated neurotoxicity in situations like ischemic stroke and traumatic brain injury, but were unsuccessful in clinical trials. 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External links Media related to NMDA receptor at Wikimedia Commons NMDA receptor pharmacology Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit A schematic diagram summarizes three potential models for the switching of NR2A and NR2B subunits at developing synapses Drosophila NMDA receptor 1 - The Interactive Fly Ion channel, cell surface receptor : ligand - gated ion channels Cys - loop receptors 5 - HT / serotonin 5 - HT GABA GABA α α α α α α β β β γ γ γ δ ε π θ GABA - ρ ρ ρ ρ Glycine α α α α β Nicotinic acetylcholine monomers : α1 α2 α3 α4 α5 α6 α7 α9 α10 β1 β2 β3 β4 δ ε pentamers : ( α3 ) ( β4 ) ( α4 ) ( β2 ) ( α7 ) ( α1 ) ( β4 ) - Ganglion type ( α1 ) β1δε - Muscle type Zinc Zinc - activated Ionotropic glutamates Ligand - gated only AMPA ( 1 4 ) Kainate 5 Voltage - and ligand - gated NMDA 2A 2B 2C 2D 3A 3B L1A L1B ' Orphan ' GluD δ δ ATP - gated channels Purinergic receptors P2X 5 6 7 Ionotropic glutamate receptor modulators AMPAR Agonists : Main site agonists : 5 - Fluorowillardiine Acromelic acid ( acromelate ) AMPA BOAA Domoic acid Glutamate Ibotenic acid Proline Quisqualic acid Willardiine ; Positive allosteric modulators : Aniracetam Cyclothiazide CX - 516 CX - 546 CX - 614 Farampator ( CX - 691, ORG - 24448 ) CX - 717 CX - 1739 CX - 1942 Diazoxide Hydrochlorothiazide ( HCTZ ) IDRA - 21 LY - 392098 LY - 395153 LY - 404187 LY - 451646 LY - 503430 Mibampator ( LY - 451395 ) Nooglutyl ORG - 26576 Oxiracetam PEPA PF - 04958242 Piracetam Pramiracetam S - 18986 Tulrampator ( S - 47445, CX - 1632 ) Antagonists : ACEA - 1011 ATPO Becampanel Caroverine CNQX Dasolampanel DNQX Fanapanel ( MPQX ) GAMS Kaitocephalin Kynurenic acid Kynurenine Licostinel ( ACEA - 1021 ) NBQX PNQX Selurampanel Tezampanel Theanine Topiramate YM90K Zonampanel ; Negative allosteric modulators : Barbiturates ( e.g., pentobarbital, sodium thiopental ) Cyclopropane Enflurane Ethanol ( alcohol ) Evans blue GYKI - 52466 GYKI - 53655 Halothane Irampanel Isoflurane Perampanel Pregnenolone sulfate Sevoflurane Talampanel ; Unknown / unsorted antagonists : Minocycline KAR Agonists : Main site agonists : 5 - Bromowillardiine 5 - Iodowillardiine Acromelic acid ( acromelate ) AMPA ATPA Domoic acid Glutamate Ibotenic acid Kainic acid LY - 339434 Proline Quisqualic acid SYM - 2081 ; Positive allosteric modulators : Cyclothiazide Diazoxide Enflurane Halothane Isoflurane Antagonists : ACEA - 1011 CNQX Dasolampanel DNQX GAMS Kaitocephalin Kynurenic acid Licostinel ( ACEA - 1021 ) LY - 382884 NBQX NS102 Selurampanel Tezampanel Theanine Topiramate UBP - 302 ; Negative allosteric modulators : Barbiturates ( e.g., pentobarbital, sodium thiopental ) Enflurane Ethanol ( alcohol ) Evans blue NS - 3763 Pregnenolone sulfate NMDAR Agonists : Main site agonists : AMAA Aspartate Glutamate Homocysteic acid ( L - HCA ) Homoquinolinic acid Ibotenic acid NMDA Proline Quinolinic acid Tetrazolylglycine Theanine ; Glycine site agonists : β - Fluoro - D - alanine ACBD ACC ( ACPC ) ACPD AK - 51 Apimostinel ( NRX - 1074 ) B6B21 CCG D - Alanine D - Cycloserine D - Serine DHPG Dimethylglycine Glycine HA - 966 L - 687414 L - Alanine L - Serine Milacemide Neboglamine ( nebostinel ) Rapastinel ( GLYX - 13 ) Sarcosine ; Polyamine site agonists : Neomycin Spermidine Spermine ; Other positive allosteric modulators : 24S - Hydroxycholesterol DHEA ( prasterone ) DHEA sulfate ( prasterone sulfate ) Epipregnanolone sulfate Pregnenolone sulfate SAGE - 718 Antagonists : Competitive antagonists : AP5 ( APV ) AP7 CGP - 37849 CGP - 39551 CGP - 39653 CGP - 40116 CGS - 19755 CPP Kaitocephalin LY - 233053 LY - 235959 LY - 274614 MDL - 100453 Midafotel ( d - CPPene ) NPC - 12626 NPC - 17742 PBPD PEAQX Perzinfotel PPDA SDZ - 220581 Selfotel ; Glycine site antagonists : 4 - Cl - KYN ( AV - 101 ) 5, 7 - DCKA 7 - CKA ACC ACEA - 1011 ACEA - 1328 Apimostinel ( NRX - 1074 ) AV - 101 Carisoprodol CGP - 39653 CNQX D - Cycloserine DNQX Felbamate Gavestinel GV - 196771 Harkoseride Kynurenic acid Kynurenine L - 689560 L - 701324 Licostinel ( ACEA - 1021 ) LU - 73068 MDL - 105519 Meprobamate MRZ 2 / 576 PNQX Rapastinel ( GLYX - 13 ) ZD - 9379 ; Polyamine site antagonists : Arcaine Co 101676 Diaminopropane Diethylenetriamine Huperzine A Putrescine ; Uncompetitive pore blockers ( mostly dizocilpine site ) : 2 - MDP 3 - HO - PCP 3 - MeO - PCE 3 - MeO - PCMo 3 - MeO - PCP 4 - MeO - PCP 8A - PDHQ 18 - MC α - Endopsychosin Alaproclate Alazocine ( SKF - 10047 ) Amantadine Aptiganel Argiotoxin - 636 Arketamine ARL - 12495 ARL - 15896 - AR ARL - 16247 Budipine Coronaridine Delucemine ( NPS - 1506 ) Dexoxadrol Dextrallorphan Dextromethadone Dextromethorphan Dextrorphan Dieticyclidine Diphenidine Dizocilpine Ephenidine Esketamine Etoxadrol Eticyclidine Fluorolintane Gacyclidine Ibogaine Ibogamine Indantadol Ketamine Ketobemidone Lanicemine Levomethadone Levomethorphan Levomilnacipran Levorphanol Loperamide Memantine Methadone Methorphan Methoxetamine Methoxphenidine Milnacipran Morphanol NEFA Neramexane Nitromemantine Noribogaine Norketamine Orphenadrine PCPr PD - 137889 Pethidine ( meperidine ) Phencyclamine Phencyclidine Propoxyphene Remacemide Rhynchophylline Rimantadine Rolicyclidine Sabeluzole Tabernanthine Tenocyclidine Tiletamine Tramadol ; Ifenprodil ( NR2B ) site antagonists : Besonprodil Buphenine ( nylidrin ) CO-101244 ( PD - 174494 ) Eliprodil Haloperidol Isoxsuprine Radiprodil ( RGH - 896 ) Rislenemdaz ( CERC - 301, MK - 0657 ) Ro 8 - 4304 Ro 25 - 6981 Safaprodil Traxoprodil ( CP - 101606 ) ; NR2A - selective antagonists : MPX - 004 MPX - 007 TCN - 201 TCN - 213 ; Cations : Hydrogen Magnesium Zinc ; Alcohols / volatile anesthetics / related : Benzene Butane Chloroform Cyclopropane Desflurane Diethyl ether Enflurane Ethanol ( alcohol ) Halothane Hexanol Isoflurane Methoxyflurane Nitrous oxide Octanol Sevoflurane Toluene Trichloroethane Trichloroethanol Trichloroethylene Urethane Xenon Xylene ; Unknown / unsorted antagonists : ARR - 15896 Bumetanide Caroverine D - αAA Dexanabinol Flufenamic acid Flupirtine FPL - 12495 FR - 115427 Furosemide Hodgkinsine Ipenoxazone ( MLV - 6976 ) MDL - 27266 Metaphit Minocycline MPEP Niflumic acid Pentamidine Pentamidine isethionate Piretanide Psychotridine Transcrocetin ( saffron ) See also : Receptor / signaling modulators Metabotropic glutamate receptor modulators Glutamate metabolism / transport modulators Neuroethology Concepts Feedforward Coincidence detector Umwelt Instinct Feature detection Central pattern generator ( CPG ) NMDA receptor Lateral inhibition Fixed action pattern Krogh 's Principle Hebbian theory Anti-Hebbian learning Sound localization Ultrasound avoidance in insects People Theodore Holmes Bullock Walter Heiligenberg Niko Tinbergen Konrad Lorenz Donald Griffin Donald Kennedy Karl von Frisch Erich von Holst Jörg - Peter Ewert Franz Huber Bernhard Hassenstein Werner E. Reichardt Eric Knudsen Eric Kandel Nobuo Suga Masakazu Konishi Fernando Nottebohm Methods Patch clamp Slice preparation Systems Animal echolocation Waggle dance Jamming avoidance response Vision in toads Frog hearing and communication Infrared sensing in snakes Caridoid escape reaction Vocal learning Surface wave detection Electroreception Mechanoreception Drug design Steps in design Drug discovery Hit to lead Drug development Pre-clinical Clinical Phases Case studies of discovery and development of drug classes ACE inhibitors Angiotensin receptor blockers Antiandrogens Beta - blockers Beta agonists Cephalosporins c - Met inhibitors Cyclooxygenase 2 inhibitors Dipeptidyl peptidase - 4 inhibitors Direct thrombin inhibitors Direct Xa inhibitors Dual serotonin and norepinephrine reuptake inhibitors Selective serotonin reuptake inhibitors Gliflozins HIV - protease inhibitors Integrase inhibitors Lipase inhibitors Memantine and related drugs mTOR inhibitors Neuraminidase inhibitors Non-nucleoside reverse - transcriptase inhibitors NS5A inhibitors Nucleoside and nucleotide reverse - transcriptase inhibitors PDE5 inhibitors Proton pump inhibitors Statins Thalidomide and its analogs Triptans TRPV1 antagonists Tubulin inhibitors Bcr - Abl tyrosine - kinase inhibitors Cannabinoid receptor antagonists CCR5 receptor antagonists Neurokinin 1 receptor antagonists 5 - HT antagonists Melatonin receptor agonists Renin inhibitors Retrieved from `` https://en.wikipedia.org/w/index.php?title=NMDA_receptor&oldid=805677447 '' Categories : Cell signaling Glutamate ( neurotransmitter ) Ion channels Ionotropic glutamate receptors Molecular neuroscience Drug discovery NMDA receptor antagonists Hidden categories : CS1 maint : Multiple names : authors list CS1 maint : Explicit use of et al. 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Question: which amino acid in mice was discovered to play a role in memory
Answer: glutamate