NMDA receptor antagonist

NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the NMDA receptor (NMDAR). They are used as anesthesia for animals and (less commonly) for humans, and some, such as ketamine and phencyclidine (PCP), are also popular as recreational drugs for their hallucinogenic properties. When used recreationally, they are classified as dissociative drugs, and are often considered entheogens.

Uses and effects
NMDA receptor antagonists are induce a state of called "dissociative anesthesia", which is marked by catalepsy, amnesia, and analgesia. Ketamine and other NMDA receptor antagonists are most frequently used in conjunction with diazepam as anesthesia in cosmetic or reconstructive plastic surgery and in the treatment of burn victims. Ketamine is a favored anesthetic for emergency patients with unknown medical history because it depresses breathing less than other anesthetics. The NMDA receptor antagonist dextromethorphan is one of the most commonly used cough supressants in the world.

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 inadequate NMDA receptor function (the "glutamate hypothesis" of schizophrenia). 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 induce dissociation and hallucinations.

NMDA receptor antagonist neurotoxicity
Exposure to NMDA receptor antagonists can cause a serious brain damage in the cingulate cortex and retrosplinial cortex regions of the brain. The experimental NMDA receptor antagonist MK-801 has been shown to cause neural vacuolization in test rats that later develop into irreversible lesions called "Olney's Lesions." Several drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists, such as 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. However, because of the neurotoxicity caused by NMDA receptor antagonists, research has slowed and studies have started to find agents that prevent this neurotoxicity. <ref name= 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. This interference with normal function could be responsible for neuronal death that sometimes results from NMDA receptor antagonist use.

Pharmacology of blockade


Different drugs inhibit NMDA receptors in different ways. Competitive antagonists block sites to which the neurotransmitter glutamate binds and activates receptors. Similarly, glycine antagonists block the site to which glycine binds to activate NMDA receptors. Noncompetitive antagonists prevent the NMDA receptor from activating by binding to allosteric sites, whereas uncompetitive antagonists physically block the channel in the NMDA receptor through which ions flow by occupying it.

Examples
Uncompetitive channel blockers include:
 * Amantadine
 * Dextromethorphan
 * Dextrorphan
 * Dizocilpine (MK-801)
 * Ibogaine
 * Ketamine
 * Nitrous Oxide
 * Phencyclidine
 * Riluzole
 * Tiletamine

Noncompetitive antagonists include:
 * Aptiganel (Cerestat, CNS-1102). Binds the Mg2+ binding site within the channel of the NMDA receptor.
 * Memantine (Axura®, Akatinol®, Namenda®, Ebixa®, 1-amino-3,5-dimethylada-mantane). Moderate affinity, voltage-dependent uncompetitive antagonist.  Approved in the U.S. by the Food and Drug Administration for the treatment of Alzheimer's disease.
 * Remacimide. Principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.

Glycine antagonists (drugs that act at the glycine binding site) include:
 * 7-chlorokynurenate
 * DCKA (5,7-dichlorokynurenic)

Competitive antagonists include:
 * AP7 (2-amino-7-phosphonoheptanoic acid)
 * APV (R-2-amino-5-phosphonopentanoate)
 * CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid)