NMDA receptor antagonist
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 anesthetics for animals and 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 adult primates like humans. Recent research conducted on primates suggests that, while very consistent and long-term ketamine use may be neurotoxic, acute use is not.
Some NMDA receptor antagonists, such as ketamine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), are popular recreational drugs used 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 (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, though these effects and the strength thereof vary from drug to drug.
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.
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 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. Indeed, a 2009 review found no evidence of ketamine-induced neuron death in humans. Temporary cognitive impairment seems to occur, though. 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 agonists 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, 5-HT2A serotonin receptor agonists, and muscimol.
Potential for treatment of 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 withdrawal, 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, 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 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.
- 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
- Amantadine: used for treating Parkinson's disease and influenza and Alzheimer's.
- Atomoxetine: a norepinephrine reuptake inhibitor used in the treatment of ADHD.
- Agmatine: Blocks NMDA receptors and other cation ligand-gated channels. Can also potentiate opioid analgesia.
- Chloroform: an early anesthetic.
- Dextrallorphan: a more potent analogue of dextromethorphan.
- Dextromethorphan: a common antitussive found in cough medicines.
- Dextrorphan: active metabolite of dextromethorphan.
- Diphenidine: a novel designer drug sold on the internet.
- Dizocilpine (MK-801): an experimental drug used in scientific research.
- 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.
- Memantine: treatment for Alzheimer's disease.
- Methoxetamine: a novel designer drug sold on the internet.
- Nitromemantine: a novel memantine derivative.
- Nitrous oxide: used for anesthesia, particularly in dentistry.
- Phencyclidine: a Schedule II controlled substance in the United States.
- 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.
- Neramexane: a memantine analogue with nootropic, antidepressant properties. Also a nicotinic acetylcholine antagonist.
- 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: 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.
- 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 antidepressant 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
These drugs act at the glycine binding site:
- Rapastinel (GLYX-13) (weak partial agonist; 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 (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.
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