, one of the most common NMDA receptor antagonists.
NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor (NMDAR). They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia. There is evidence that NMDA receptor antagonists can cause a certain type of neurotoxicity or brain damage referred to as Olney's Lesions in rodents, although such damage has never been conclusively observed in primates like humans, however, in adolescent cynomolgus monkeys that were injected daily with the non-competitive NMDA antagonist, ketamine, there were some definite neurologic deficits observed.
Several synthetic opioids function additionally as NMDAR-antagonists, such as Meperidine, Methadone, Dextropropoxyphene, Tramadol and Ketobemidone.
Some NMDA receptor antagonists, including but not limited to ketamine (K), dextromethorphan (DXM), phencyclidine (PCP), and nitrous oxide (N2O) are popular as recreational drugs for their dissociative, hallucinogenic, and/or euphoriant properties. When used recreationally, they are classified as dissociative drugs.
Uses and effects 
NMDA receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia. Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics. Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world), is known to be an NMDA receptor antagonist.
Depressed NMDA receptor function is associated with an array of negative symptoms. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging. Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia).Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis".NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis.Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia, ataxia, anaesthesia, and learning and memory deficits.
Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects, and at higher doses, begin inducing dissociation and hallucinations.
Most NMDA receptor antagonists are metabolized in the liver. Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.
Exposure to NMDA receptor antagonists may cause severe brain damage in the cingulate cortex and retrosplenial cortex regions of the brain, but evidence towards this hypothesis is not very strong at the moment. The correlation observed, however, does make sense given the profound abnormalities in bilateral communication between brain hemispheres observed in NMDA antagonist intoxication. In high doses, almost no glutaminergic activity is observed within the corpus callosum, naturally a region primarily GABAergic. Given a sufficiently long duration of action of the ligand, abnormalities develop in hemisphere communication. The cingulate cortex shifts its balance towards the posterior, where hemispheric communication is much more deeply ingrained, due to depth perception. Through long-term potentiation (LTP) and long-term depression (LTD), this can become permanent with regular administration. While gross structural abnormalities are yet to be observed in humans, likely due to the lack of studies with people under continuous administration, significant cognitive deficits are observed in those who regularly abuse dissociatives. Constant antagonism of NMDA, the primary neurotransmitter involved in LTP, and a major contributor to LTD, results in profound, permanent synaptic abnormalities, even in relatively low doses. The experimental NMDA and nicotinic acetylcholine receptor antagonist MK-801 has been shown to cause neural vacuolization in test rodents that later develop into irreversible lesions called "Olney's Lesions." Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most specifically target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates, ethanol, 5-HT2A serotonin agonists, and muscimol.
Potential for treatment of excitotoxicity 
Since NMDA receptors are one of the most harmful factors in excitotoxicity, antagonists of the receptors have held much promise for the treatment of conditions that involve excitotoxicity, including traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions, (which have only ever been observed in rodents, due to their lack of enzymes needed to break NMDA receptor antagonists down) although there is significant evidence against Olney's lesions forming in humans, and studies have started to find agents that prevent this neurotoxicity. Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic function, blocking them has harmful effects. These results have not yet been reproduced in humans, however. This interference with normal function could be responsible for neuronal death that sometimes results from NMDA receptor antagonist use.
Mechanism of action 
Simplified model of NMDAR activation and various types of NMDAR blockers.
The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."
Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate; glycine antagonists, which bind to and block the glycine site; noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists, which block the ion channel by binding to a site within it.
Competitive antagonists 
- AP5 (APV, R-2-amino-5-phosphonopentanoate)
- AP7 (2-amino-7-phosphonoheptanoic acid)
- CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid)
- Selfotel: an anxiolytic, anticonvulsant but with possible neurotoxic effects.
Uncompetitive channel blockers 
Non-competitive antagonists 
- Aptiganel (Cerestat, CNS-1102): binds the Mg2+ binding site within the channel of the NMDA receptor.
- HU-211: an enantiomer of the potent cannabinoid HU-210 which lacks cannabinoid effects and instead acts as a potent non-competitive NMDA antagonist.
- Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.
- Rhynchophylline an alkaloid.
- Ketamine: a dissociative psychedelic with depressant properties used as an anesthesia in humans and animals, a possible treatment in bipolar disorder patients with Treatment-resistant depression, and used recreationally for its effects on the CNS
Glycine antagonists 
These drugs act at the glycine binding site:
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- Agonists: Glutamate/acite site competitive agonists: Aspartate
- Homoquinolinic acid
- Ibotenic acid
- Quinolinic acid
- Tetrazolylglycine; Glycine site agonists: ACBD
- Tetrazolylglycine; Polyamine site agonists: Acamprosate
Antagonists: Competitive antagonists: AP5 (APV)
- Midafotel (d-CPPene)
- Selfotel; Noncompetitive antagonists: ARR-15,896
- Zinc; Uncompetitive pore blockers: 2-MDP
- Meperidine (Pethidine)
- Methadone (Levomethadone)
- Methorphan (Dextromethorphan
- Morphanol (Dextrorphan
- Nitrous oxide
- Xenon; Glycine site antagonists: ACEA-1021
- Kynurenic acid
- MRZ 2/576
- ZD-9379; NR2B subunit antagonists: Besonprodil
- CO-101,244 (PD-174,494)
- Traxoprodil; Polyamine site antagonists: Arcaine
- Co 101676
- Huperzine A
- Ro 25-6981; Unclassified/unsorted antagonists: Chloroform
- Diethyl ether
- Ethanol (alcohol)