An NMDA receptor antagonist is a compound in a family of psychoactive drugs, mainly anesthetics and anticonvulsants, which inhibit (antagonize) the NMDA (N-methyl D-aspartate) receptor. The NMDAR is a glutamate receptor which is responsible for regulating synaptic plasticity and memory.

Clinically, their main role is use in both human and animal anesthesia, epilepsy, depression and neuropathic pain. They can be considered as entheogens for their spiritual use as well as recreational drugs. When used in quantities insufficient for anesthesia, they can cause hallucinogenic and dissociative effects as well as euphoria.

The toxicity of NMDA receptor antagonists varies greatly from substance to substance, as well as with different species. The most common issue cited is the formation of Olney's lesions, a type of neurotoxic damge, in rodents, although no documented cases have been reported in humans.[1]

[top]Competitive

Competitive antagonists bind to the glutamate or glycine sites on the NMDA receptor and prevent those respective endogenous compounds from binding and activating the receptor.

[top]Glutamate Site

This includes competitive antagonists that bind to the glutamate site on the NMDA receptor bind instead of glutamate.

[top]AP5

Fast acting and potent antagonist used in research.

[top]AP7

Potent antagonist with anticonvulsant effects in rats.

[top]CGP-37849

Potent antagonist with anticonvulsant and neuroprotective effects.

[top]Midafotel (CPPene)

Initially developed for epilepsy or neuropathic pain, but discontinued due to disappointing clinical trials.

[top]Selfotel

Initially developed for stroke, but discontinued due to concerns about neurotoxicity.

[top]Glycine Site

Competitive antagonists that bind to the glycine site on the NMDA receptor bind instead of glycine. Therefore they also prevent activation of the NMDA receptor by blocking glycine from activating it.

[top]Felbamate

An anticonvulsant that has resulted in rare (but serious) cases of aplastic anemia and liver failure. Current use is limited to severe epilepsy.

[top]Kynurenic acid

A naturally occurring antagonist.

[top]Lacosamide

Used for epilepsy and diabetic neuropathic pain.

[top]NonCompetitive

Noncompetitive antagonists bind at an allosteric site on the receptor, which is different from the glycine or glutamate site. These antagonists inactivate the receptor without blocking the active sites.

[top]Ketamine

An anesthetic mainly used in veterinary practice but sometimes still used in humans.

[top]Remacemide

An anticonvulsant which acts as a sodium channel blocker.

[top]Uncompetitive

Also known as channel blockers, these bind inside the NMDA receptor in place of magnesium (which usually acts as a low affinity antagonist).

[top]Amantadine

Antiviral drug used to treat parkinson's.

[top]Dextromethorphan

Main article: Dextrorphan

Over the counter cough suppressant.

[top]Dextrorphan

Main article: Dextrorphan

Metabolite of dextromethorphan.

[top]Dizocilpine

Main article: Dizocilpine (MK-801)

A very potent antagonist commonly used in animal studies.

[top]Ibogaine

A schedule I substance in the US that has psychedelic and anti-addictive properties.

[top]Memantine

Main article: Memantine

Used to treat symptoms of Alzheimer's.

[top]Neramexane

Analog of Memantine.

[top]Phencyclidine

Main article: Phencyclidine (PCP)

Previously used as a human and veterinary anesthetic.

[top]Tiletamine

Used as an animal anesthetic; usually combined with zolazepam.

[top]Unknown

[top]Carbamazepine

An anticonvulsant and mood-stabilizer.

[top]Huperzine A

Acetylcholinesterase inhibitor which may be beneficial for Alzheimer's.

[top]Methoxetamine

A ketamine analogue with a short history of recreational use.

[top]Other

Competitive antagonists: CGP-39551, CGP-39653, CGP-40116, CGS-19755, CPP, LY-233,053, LY-235,959, LY-274,614, MDL-100,453, NPC-12,626, NPC-17,742, PBPD, PEAQX, Perzinfotel, PPDA, SDZ-220581
Glycine site antagonists: ACEA-1021, ACEA-1328, ACPC, Carisoprodol, CGP-39653, CKA, DCKA, Gavestinel, GV-196,771, L-689,560, L-701,324, Licostinel, LU-73,068, MDL-105,519, Meprobamate, MRZ 2/576, PNQX, ZD-9379
Noncompetitive antagonists: ARR-15,896, Caroverine, Dexanabinol, FPL-12495, FR-115,427, Hodgkinsine, Magnesium, MDL-27,266, NPS-1506, Psychotridine, Zinc
Uncompetitive pore blockers: 2-MDP, 3-MeO-PCP, 8A-PDHQ, Alaproclate, Aptiganel, ARL-12,495, ARL-15,896-AR, ARL-16,247, Budipine, Delucemine (NPS 1506), Dexoxadrol, Dextrallorphan, Dieticyclidine, Endopsychosin, Esketamine, Etoxadrol, Eticyclidine, Gacyclidine, Indantadol, Ketamine, Ketobemidone, Loperamide, Meperidine (Pethidine), Methadone, Milnacipran, Morphanol (Dextrorphan, Levorphanol), NEFA, Nitrous oxide, Noribogaine, Orphenadrine, PCPr, Phencyclamine, Propoxyphene, Remacemide, Rhynchophylline, Riluzole, Rimantadine, Rolicyclidine, Sabeluzole, Tenocyclidine, Tramadol, Xenon
NR2B subunit antagonists: Besonprodil, CO-101,244 (PD-174,494), CP-101,606, Eliprodil, Haloperidol, Ifenprodil, Isoxsuprine, Nylidrin, Ro8-4304, Ro25-6981, Traxoprodil
Polyamine site antagonists: Arcaine, Co 101676, Diaminopropane, Acamprosate, Diethylenetriamine, Huperzine A, Putrescine, Ro 25-6981
Unclassified/unsorted antagonists: Chloroform, Diethyl ether, Enflurane, Ethanol (Alcohol), Halothane, Isoflurane, Methoxyflurane, Toluene, Trichloroethane, Trichloroethanol, Trichloroethylene, Xylene, NPS 1407, NPS 1392, L-theanine

Common NMDA Receptor Antagonists [2]

^ Anderson, Cliff. "Erowid DXM Vaults : Health : The Bad News Isn't In : A Look at Dissociative-Induced Brain Damage, by Anderson C." Erowid. June 2003. Version 2.2. Web. 18 Aug. 2010.
^ http://dx.doi.org/10.1016/j.yebeh.2011.07.024

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