NMDA receptor antagonist

Ketamine, 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, though such damage has never been observed in primates like humans.

Several synthetic opioids function additionally as NMDA-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.^[1] 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.^[2][3] The NMDA receptor antagonist dextromethorphan is one of the most commonly used cough suppressants in the world.^[4]

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.^[5] Schizophrenia may also have to do with irregular NMDA receptor function (the glutamate hypothesis of schizophrenia).^[6]Increased levels of another NMDA antagonist, kynurenic acid, may aggravate the symptoms of schizophrenia, according to the "kynurenic hypothesis".^[7]NMDA receptor antagonists can mimic these problems; they sometimes induce "psychotomimetic" side effects, symptoms resembling psychosis.^[8]Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares,^[9] catatonia,^[10] ataxia,^[11] anaesthesia,^[12] and learning and memory deficits.^[13]

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.^[14]

Most NMDA receptor antagonists are metabolized in the liver.^[15][16] Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.^[17]

Neurotoxicity

Main article: Olney's lesions

Exposure to NMDA receptor antagonists may cause serious 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 experimental NMDA receptor antagonist MK-801 has been shown to cause neural vacuolization in test rodents that later develop into irreversible lesions called "Olney's Lesions."^[18][19] 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,^[20] ethanol,^[21] 5-HT_2A serotonin agonists,^[22] and muscimol.^[23]

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,^[24] although there is evidence against Olney's lesions forming in humans, and studies have started to find agents that prevent this neurotoxicity.^[23][21] 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. William White once wrote a paper on the "potential" dangers of these lesions but later retracted his hypothesis as "depression-induced nonsense".^{[25][unreliable source?][26]} This interference with normal function could be responsible for neuronal death that sometimes results from NMDA receptor antagonist use.^[27]

Mechanism of action

Simplified model of NMDAR activation and various types of NMDAR blockers.^[11]

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, an NMDA receptor must bind to glutamate and to glycine. An NMDA receptor that is bound to glycine and glutamate 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.^[11]

Examples

Competitive antagonists

• AP5 (APV, R-2-amino-5-phosphonopentanoate)^[28]
• AP7 (2-amino-7-phosphonoheptanoic acid)^[29]
• CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid)^[30]
• Selfotel: an axiolytic, anticonvulsant but with possible neurotoxic effects.

Uncompetitive channel blockers

• Amantadine: used for treating Parkinson's disease and influenza and Alzheimer's.^[31][32]
• Dextrallorphan: a more potent analogue of dextromethorphan.
• Dextromethorphan: a common antitussive found in cough medicines.^[33]
• Dextrorphan: active metabolite of dextromethorphan.
• Dizocilpine (MK-801): an experimental drug used in scientific research.^[34]
• Ethanol: also known as alcohol, a widely used legal intoxicant.
• Eticyclidine: a Schedule I controlled substance in the United States.
• Gacyclidine: an experimental drug developed for neuroprotection.
• Ibogaine: a Schedule I controlled substance in the United States.^[35][36]
• Magnesium
• Memantine: treatment for Alzheimer's disease.^[37]
• Methoxetamine: a novel designer drug sold on the internet.^{[citation needed]}
• Nitrous oxide: used for anesthesia, particularly in dentistry.^[38]
• Phencyclidine: a Schedule II controlled substance in the United States.^[35]
• Rolicyclidine: a Schedule I controlled substance in the United States.
• Tenocyclidine: a Schedule I controlled substance in the United States.
• Methoxydine: 4-meo-pcp
• Tiletamine: an animal anesthetic.^[39]
• Xenon: an anesthetic.
• Neramexane: a memantine analogue with nootropic, antidepressant properties. Also a nicotinic acetylcholine antagonist.
• Eliprodil: an anticonvulsant with neuroprotective drug.
• Etoxadrol: a potent dissociative similar to PCP.
• Dexoxadrol: similar to etoxadrol.
• NEFA: a moderate affinity antagonist.
• Remacemide: a low affinity antagonist also a sodium-channel blocker.
• Delucemine: also a SSRI with neuroprotective properties.
• 8A-PDHQ: a high affinity PCP structural analogue.

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.^[40]
• Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.^[41]
• Rhynchophylline an alkaloid.
• Ketamine: an animal and human anesthetic and recreational drug.^[42]

Glycine antagonists

These drugs act at the glycine binding site:

• 1-Aminocyclopropanecarboxylic acid (ACPC)
• 7-Chlorokynurenate^[43]
• DCKA (5,7-dichlorokynurenic acid)^[44]
• Kynurenic acid: a naturally occurring antagonist^[45]
• Lacosamide: an investigational drug for the treatment of epilepsy and diabetic neuropathic pain.^[46]

See also

Neuroscience portal

• Neurotransmitters
• Psychedelics
• Long-term potentiation
• NMDA

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