NMDA receptor antagonists are a class of

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (

NMDAR The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

). They are commonly used as

anesthetics An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

for animals and humans; the state of

anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...

they induce is referred to as

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

anesthesia. Several synthetic opioids function additionally as NMDAR-antagonists, such as

pethidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid analgesic, pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemis ...

levorphanol Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan. It was first described in German ...

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroin ...

dextropropoxyphene Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive (cough suppressant) ...

tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...

and

ketobemidone Ketobemidone, sold under the brand name Ketogan among others, is a powerful synthetic opioid painkiller. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA-antagonist properties imparted, in part, by its m ...

. Some NMDA receptor antagonists, such as

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...

dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...

(DXM),

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptio ...

(PCP),

methoxetamine Methoxetamine, abbreviated as MXE, is a dissociative hallucinogen that has been sold as a designer drug. It differs from many dissociatives such as ketamine and phencyclidine (PCP) that were developed as pharmaceutical drugs for use as general ...

(MXE), and

nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and has a ...

(N₂O), are sometimes used as

recreational drug Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...

s, for their dissociative,

hallucinogen Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorized ...

ic, and

euphoriant Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

properties. When used recreationally, they are classified as

dissociative drug Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

Uses and effects

NMDA receptor antagonists induce a state called

dissociative anesthesia Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

, marked by

catalepsy Catalepsy (from Ancient Greek , , "seizing, grasping") is a nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain. Signs and symptoms Symptoms in ...

amnesia Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use ...

, and

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

. 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 Dextrorphan (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. D ...

, a metabolite of

(one of the most commonly used

cough suppressant Cold medicines are a group of medicinal, medications taken individually or in Combination drug, combination as a Symptomatic treatment, treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The t ...

s 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 Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

Schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

may also have to do with irregular NMDA receptor function (the

glutamate hypothesis of schizophrenia The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings point ...

). Increased levels of another NMDA antagonist,

kynurenic acid Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid -tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an ...

, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis". NMDA receptor antagonists can mimic these problems; they sometimes induce "

psychotomimetic A drug with psychotomimetic (also known as psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms following the administrat ...

" side effects, symptoms resembling

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

. Such side effects caused by NMDA receptor inhibitors include

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...

paranoid delusion Delusional disorder is a mental illness in which a person has delusions, but with no accompanying prominent hallucinations, thought disorder, mood disorder, or significant flattening of affect.American Psychiatric Association. (2013). ''Diagnost ...

confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"

, difficulty concentrating, agitation, alterations in mood,

nightmare A nightmare, also known as a bad dream, Retrieved 11 July 2016. is an unpleasant dream that can cause a strong emotional response from the mind, typically fear but also despair, anxiety or great sadness. The dream may contain situations of d ...

catatonia Catatonia is a complex neuropsychiatric behavioral syndrome that is characterized by abnormal movements, immobility, abnormal behaviors, and withdrawal. The onset of catatonia can be acute or subtle and symptoms can wax, wane, or change during ...

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

, and

learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machine learning, machines ...

and

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...

deficits. Because of these psychotomimetic effects, NMDA receptor antagonists, especially

, and

, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug. Most NMDA receptor antagonists are

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

in the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

. Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream. NMDA receptor antagonists are also under investigation as antidepressants. Ketamine, in particular, has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019

esketamine Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the ''S''(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand n ...

, an NMDA antagonist

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

of ketamine, was approved for use as an antidepressant in the United States.

Neurotoxicity

Although NMDA antagonists were once thought to reliably cause neurotoxicity in humans in the form of Olney's lesions, recent research suggests otherwise. Olney's lesions involve mass

vacuolization Vacuolization is the formation of vacuoles or vacuole-like structures, within or adjacent to cells. Perinuclear vacuolization of epidermal keratinocytes is most likely inconsequential when not observed in combination with other pathologic find ...

of neurons observed in rodents. However, many suggest that this is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity. A 2009 review found no evidence of ketamine-induced neuron death in humans. However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not. Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s such as

clonidine Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and c ...

and

guanfacine Guanfacine, sold under the brand name Tenex among others, is an oral medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure. Guanfacine is FDA-approved for monotherapy treatment of ADHD as well as being ...

are thought to most directly target the

etiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...

of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include:

anticholinergics Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sy ...

diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...

, barbiturates,

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

, 5-HT_2A

serotonin receptor agonist A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the ...

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

s, and

muscimol Muscimol (also known as agarin or pantherine) is one of the principal psychoactive constituents of '' Amanita muscaria'' and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptors and displa ...

Potential for treatment of excess excitotoxicity

Since NMDA receptor overactivation is implicated in

excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...

, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal,

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic b ...

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

, and

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

s such as

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

Parkinson's Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

, and Huntington's. This is counterbalanced by the risk of developing

Olney's lesions Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAN), are a form of potential brain damage due to drugs that have been studied experimentally and have produced neuronal damage, yet are administered by doctors to humans in the ...

, which have only ever been observed in rodents, 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 Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonis ...

neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however. Mild NMDA receptor antagonists like

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

have been found to be helpful in benzodiazepine withdrawal.

Mechanism of action

The NMDA receptor is an

ionotropic receptor Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

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 Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

and

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

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 antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of r ...

s, which bind to and block the binding site of the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

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.

Examples

Competitive antagonists

* AP5 (APV, R-2-amino-5-phosphonopentanoate). * AP7 (2-amino-7-phosphonoheptanoic acid). * CGP-37849 * CPPene (3- R)-2-carboxypiperazin-4-ylprop-2-enyl-1-phosphonic acid). *

Selfotel Selfotel (CGS-19755) is a drug which acts as a competitive NMDA antagonist, directly competing with glutamate for binding to the receptor. Initial studies showed it to have anticonvulsant, anxiolytic, analgesic and neuroprotective effects, and ...

: an anxiolytic, anticonvulsant but with possible neurotoxic effects. *

Aspartame Aspartame is an artificial non-saccharide sweetener 200 times sweeter than sucrose and is commonly used as a sugar substitute in foods and beverages. It is a methyl ester of the aspartic acid/phenylalanine dipeptide with the trade names ...

: an artificial sweetener, however not as strongly as the amino acid

Aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

Uncompetitive channel blockers

* 3-MeO-PCP: an analogue of PCP * 8A-PDHQ: a high affinity PCP structural analogue. *

Amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wi ...

: used for treating

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...

, and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

. *

Atomoxetine Atomoxetine, sold under the brand name Strattera, among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD). It may be used alone or along with psychostimulants. It is also used as a cognitive enhancer to impro ...

: a

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epin ...

used in the treatment of

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

. * AZD6765. *

Agmatine Agmatine, also known as 4-aminobutyl-guanidine, is an aminoguanidine that was discovered in 1910 by Albrecht Kossel. Agmatine is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modula ...

: Blocks NMDA receptors and other cation ligand-gated channels. Can also potentiate opioid analgesia. *

Argiotoxin Argiotoxins represent a class of polyamine toxins isolated from the orb-weaver spider ('' Araneus gemma'' and '' Argiope lobata''). The orb-weaver spiders, also known aaraneids belong to the Araneidae spider family. This type of spider is found i ...

: polyamine toxins produced by the orb-weaver spider (''

Araneus gemma ''Araneus gemma'', commonly known as the cat-faced spider (a name shared with '' Araneus gemmoides''), is a common outdoor orb-weaver spider found in the western United States and Canada. Like most Araneus species, ''A. gemma'' is harmless to h ...

''and ''

Argiope lobata ''Argiope lobata'' is a species of spider belonging to the family Araneidae. It has a wide distribution encompassing the whole of Africa and stretching to southern Europe and into Asia. The male of this species is small (body length 6 mm) ...

'') *

Chloroform Chloroform, or trichloromethane, is an organic compound with chemical formula, formula Carbon, CHydrogen, HChlorine, Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to ...

: an early anesthetic. *

Cyclopropane Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane itself ...

: an early anesthetic. * Delucemine: also an SSRI with neuroprotective properties. *

Desflurane Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (''R'') and (''S'') optical i ...

: an

inhalational anesthetic An inhalational anesthetic is a chemical compound possessing general anesthetic properties that can be delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vapo ...

. * Dextrallorphan: a more potent analogue of dextromethorphan. *

Dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...

: an

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ...

found in OTC cough medicines. *

: active metabolite of dextromethorphan. * Dextromethadone: (''S'')-enantiomer of the drug

Methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroin ...

that has low affinity for opioid receptors and exhibits rapid antidepressant effects in animal models. *

Diphenidine Diphenidine (1,2-DEP, DPD, DND) is a dissociative anesthetic that has been sold as a designer drug. The synthesis of diphenidine was first reported in 1924, and employed a Bruylants reaction analogous to the one that would later be used to discov ...

: a

designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. Des ...

and PCP analogue sold on the internet. *

Dizocilpine Dizocilpine (INN), also known as MK-801, is a pore blocker of the ''N''-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is ...

(MK-801): an experimental drug used in scientific research. *

Ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

: also known as alcohol, a widely used intoxicant. *

Eticyclidine Eticyclidine (PCE, CI-400) is a dissociative anesthetic drug with hallucinogenic effects. It is similar in effects to phencyclidine but is slightly more potent. PCE was developed by Parke-Davis in the 1970s and evaluated for anesthetic potential ...

: a slightly more potent dissociative anesthetic than phencyclidine but with greater nausea/unpleasant taste, that was discontinued early in its development due to these digestive complaints. * Gacyclidine: an experimental drug developed for neuroprotection and is being studied for the treatment of tinnitus. * Halothane: an

. * Isoflurane: an

. * Ketamine: a dissociative hallucinogen with antidepressant properties used as an anesthetic in humans and animals, a possible treatment in bipolar disorder patients with Treatment-resistant depression, and used recreationally for its effects on the CNS. * Magnesium. * Memantine: treatment for Alzheimer's disease. * Methoxetamine: a novel designer drug sold on the internet. * Methoxydine: 4-MeO-PCP. * Minocycline. * Neramexane: a memantine analogue with nootropic, antidepressant properties. Also a nicotinic acetylcholine antagonist. * Nitromemantine: a novel memantine derivative. * Nitrous oxide: used for anesthesia, particularly in dentistry. * PD-137889: Potent NMDA receptor antagonist with roughly 30 times the potency of ketamine. Substitutes for PCP in animal studies. * Phencyclidine: a dissociative anesthetic previously used in medicine, but its development was discontinued in the 1960s in favor of its successor ketamine due to its relatively high incidence of psychotomimetic effects. Abused recreational and legally controlled in most countries. * Remacemide: a low affinity antagonist also a sodium-channel blocker. * Rolicyclidine: a less potent analogue of phencyclidine, but seems to be seldom, if ever, abused. * Sevoflurane: an

. * Tenocyclidine: an analogue of phencyclidine that is more potent. * Tiletamine: an animal anesthetic. * Eliprodil: an anticonvulsant drug with neuroprotective properties. * Etoxadrol: a potent dissociative similar to PCP. * Dexoxadrol: similar to etoxadrol. * WMS-2539: potent fluorinated derivative of dexoxadrol. * NEFA (drug), NEFA: a moderate affinity antagonist.

Non-competitive antagonists

* Aptiganel (Cerestat, CNS-1102): binds the magnesium, 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. *Huperzine A. *Dipeptide D-Phe-L-Tyr. weakly inhibit NMDA/Gly-induced currents possibly by ifenprodil-like mechanism. * Ibogaine: a naturally-occurring alkaloid found in plants of the family Apocynaceae. Has been used, albeit with limited evidence, to treat opioid and other addictions. * Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site. * Rhynchophylline an alkaloid, found in Kratom and Rubiaceae. * Gabapentin: a calcium a2-d ligand that is commonly used in diabetic neuropathy.

Glycine antagonists

These drugs act at the glycine binding site: * Rapastinel (GLYX-13) (weak partial agonist; intrinsic activity, IA = ~20%). * NRX-1074 (weak partial agonist). * 7-Chlorokynurenic acid. * 4-Chlorokynurenine (AV-101) (prodrug for 7-chlorokynurenic acid). * 5,7-Dichlorokynurenic acid. * Kynurenic acid (a naturally occurring antagonist). * TK-40 (drug), TK-40 (competitive antagonist at the GluN1 glycine binding site). * 1-Aminocyclopropanecarboxylic acid (ACPC). * L-Phenylalanine. a naturally occurring amino acid (equilibrium dissociation constant (K_B) from Schild regression is 573 μM). * Xenon: an anesthetic.

Potencies

Uncompetitive channel blockers

References

{{DEFAULTSORT:Nmda Receptor Antagonist Neurotrauma NMDA receptor antagonists, General anesthetics

Uses and effects

Neurotoxicity

Potential for treatment of excess excitotoxicity

Mechanism of action

Examples

Competitive antagonists

Uncompetitive channel blockers

Non-competitive antagonists

Glycine antagonists

Potencies

Uncompetitive channel blockers

See also

References