NMDA Receptor Antagonists
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NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for humans and animals; the state of
anesthesia Anesthesia (American English) or anaesthesia (British English) 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 prev ...
they induce is referred to as dissociative anesthesia. Several synthetic opioids function additionally as NMDAR-antagonists, such as pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, and ketobemidone. Some NMDA receptor antagonists, such as
ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...
,
dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
(DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), are sometimes used as recreational drugs, for their dissociative, hallucinogenic, and 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 Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
(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 ter ...
s in the world), is known to be an NMDA receptor antagonist. Numerous detrimental symptoms are linked to depressed NMDA receptor function. For example, NMDA receptor hypofunction that occurs as the brain ages may be partially responsible for memory deficits associated with aging.
Schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
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 In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
. 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 compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia,
ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
,
anesthesia Anesthesia (American English) or anaesthesia (British English) 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 prev ...
, and
learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...
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 remembe ...
deficits. Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine,
ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...
, and
dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
, 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 in the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
. 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 has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019,
esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...
, an NMDA antagonizing
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
of ketamine, was approved for use as an antidepressant in the United States. In 2022, Auvelity was approved by the FDA for the treatment of depression. This combination medication contains
dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
, an NMDA receptor antagonist.


Neurotoxicity

Olney's lesions involve mass vacuolization 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 (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates,
ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
, 5-HT2A serotonin receptor agonists, anticonvulsants, and muscimol.


Potential for treatment of excess excitotoxicity

Since NMDA receptor overactivation is implicated in excitotoxicity, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
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 (mTBI/concussion) to severe traumati ...
,
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions, and studies have started to find agents that prevent this neurotoxicity. Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however. Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal.


Mechanism of action

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 Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
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. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated." Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists block binding to
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
glutamate sites; glycine antagonists block binding to glycine sites; noncompetitive antagonists inhibit binding to NMDARs allosteric sites; and uncompetitive antagonists block binding to a site within the ion channel.


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


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 because ...
: used for treating Parkinson's disease, influenza, and
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. *
Atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...
: a norepinephrine reuptake inhibitor used in the treatment of ADHD. * AZD6765. * Agmatine: Blocks NMDA receptors and other cation ligand-gated channels. Can also potentiate opioid analgesia. * Argiotoxin: polyamine toxins produced by the orb-weaver spider ('' Araneus gemma ''and '' Argiope lobata'') * Chloroform: an early anesthetic. * Cyclopropane: an early anesthetic. * Delucemine: also an SSRI with neuroprotective properties. * Desflurane: an inhalational anesthetic. * Dextrallorphan: a more potent analogue of dextromethorphan. *
Dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
: an antitussive found in OTC cough medicines. * Dextrorphan: active metabolite of dextromethorphan. * Dextromethadone: (''S'')-enantiomer of the drug methadone that has low affinity for opioid receptors and exhibits rapid antidepressant effects in animal models. * Diphenidine: a designer drug and PCP Structural analog, analogue sold on the internet. * Dizocilpine (MK-801): an experimental drug used in scientific research. * Ethanol: also known as alcohol (drug), alcohol, a widely used intoxicant. * Eticyclidine: a slightly more potent dissociative anesthetic than phencyclidine but with greater nausea/unpleasant taste, that was discontinued early in its development due to these digestive complaints. * Gacyclidine: an experimental drug developed for neuroprotection and is being studied for the treatment of tinnitus. * Halothane: an inhalational anesthetic. * Isoflurane: an inhalational anesthetic. * Ketamine: a dissociative hallucinogen with antidepressant properties used as an anesthetic in humans and animals, a possible treatment in bipolar disorder patients with treatment-resistant depression, and used recreationally for its effects on the CNS. * 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 inhalational anesthetic. * 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 α2δ 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 (KB) from Schild regression is 573 μM). * Xenon: an anesthetic.


Potencies


Uncompetitive channel blockers


See also

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


References

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