NMDA receptor antagonist

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]


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-HT2A 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]


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

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:

See also


  1. ^ Pender J (2004). "Dissociative anesthesia". JAMA 215 (7): 1955–9. doi:10.1097/01.PRS.0000122402.52595.10. PMID 15253183. 
  2. ^ Ceber M, Salihoglu T (2006). "Ketamine may be the first choice for anesthesia in burn patients". J Burn Care Res 27 (5): 760–2. doi:10.1097/01.BCR.0000238091.41737.7C. PMID 16998413. 
  3. ^ Heshmati F, Zeinali M, Noroozinia H, Abbacivash R, Mahoori A (2003). "Use of ketamine in severe status asthmaticus in intensive care unit". Iran J Allergy Asthma Immunol 2 (4): 175–80. doi:02.04/ijaai.175180. PMID 17301376. 
  4. ^ Equinozzi R, Robuschi M (2006). "Comparative Efficacy and Tolerability of Pholcodine and Dextromethorphan in the Management of Patients with Acute, Non-Productive Cough : A Randomized, Double-Blind, Multicenter Study". Treat Respir Med 5 (6): 509–513. doi:10.2165/00151829-200605060-00014. PMID 17154678. 
  5. ^ Newcomer, JW; Krystal JH (2001). "NMDA receptor regulation of memory and behavior in humans". Hippocampus 11 (5): 529–542. doi:10.1002/hipo.1069. PMID 11732706. 
  6. ^ Lipina, T; Labrie V, Weiner I, Roder J (2005). "Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia". Psychopharmacology 179 (1): 54–67. doi:10.1007/s00213-005-2210-x. PMID 15759151. 
  7. ^ Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G (September 2007). "The kynurenic acid hypothesis of schizophrenia". Physiol. Behav. 92 (1–2): 203–9. doi:10.1016/j.physbeh.2007.05.025. PMID 17573079. http://linkinghub.elsevier.com/retrieve/pii/S0031-9384(07)00216-8. 
  8. ^ Pomarol-Clotet E, Honey GD, Murray GK, Corlett PR, Absalom AR, Lee M, McKenna PJ, Bullmore ET, Fletcher PC (August 2006). "Psychological effects of ketamine in healthy volunteers. Phenomenological study". Br J Psychiatry 189 (2): 173–9. doi:10.1192/bjp.bp.105.015263. PMID 16880489. http://bjp.rcpsych.org/cgi/pmidlookup?view=long&pmid=16880489. 
  9. ^ Muir, KW; Lees KR (1995). "Clinical Experience With Excitatory Amino Acid Antagonist Drugs". Stroke 26 (3): 503–513. doi:10.1161/01.STR.26.3.503. PMID 7886734. http://stroke.ahajournals.org/cgi/content/full/26/3/503. 
  10. ^ Aarts, MM; Tymianski M (2003). "Novel Treatment of Excitotoxicity: Targeted Disruption of Intracellular Signalling From Glutamate Receptors". Biochemical Pharmacology 66 (6): 877–886. doi:10.1016/S0006-2952(03)00297-1. PMID 12963474. 
  11. ^ a b c Kim AH, Kerchner GA, Choi DW (2002). "Blocking Excitotoxicity". In Marcoux FW, Choi DW. CNS Neuroprotection. New York: Springer. pp. 3–36. 
  12. ^ Kristensen, JD; Svensson B, and Gordh T Jr (1992). "The NMDA-Receptor Antagonist CPP Abolishes Neurogenic Wind-Up Pain After Intrathecal Administration in Humans". Pain 51 (2): 249–253. doi:10.1016/0304-3959(92)90266-E. PMID 1484720. 
  13. ^ Rockstroh, S; Emre M, Tarral A, and Pokorny R (1996). "Effects of the Novel NMDA-Receptor Antagonist SDZ EAA 494 on Memory and Attention in Humans". Psychopharmacology 124 (3): 261–266. doi:10.1007/BF02246666. PMID 8740048. 
  14. ^ Lim D (2003). "Ketamine Associated Psychedelic Effects and Dependence". Singapore Med J 44 (1): 31–34. PMID 12762561. 
  15. ^ Chia YY, Liu K, Chow LH, Lee TY (1999). "The preoperative administration of intravenous dextromethorphan reduces postoperative morphine consumption". Anesth. Analg. 89 (3): 748–52. doi:10.1097/00000539-199909000-00041. PMID 10475318. 
  16. ^ Kharasch ED, Labroo R (1992). "Metabolism of ketamine stereoisomers by human liver microsomes". Anesthesiology 77 (6): 1201–7. doi:10.1097/00000542-199212000-00022. PMID 1466470. 
  17. ^ Livingston A, Waterman AE (1978). "The development of tolerance to ketamine in rats and the significance of hepatic metabolism". Br. J. Pharmacol. 64 (1): 63–9. PMC 1668251. PMID 698482. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1668251. 
  18. ^ Olney J, Labruyere J, Price M (1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263. 
  19. ^ Hargreaves R, Hill R, Iversen L (1994). "Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology". Acta Neurochir Suppl (Wien) 60: 15–9. PMID 7976530. 
  20. ^ Olney J, Labruyere J, Wang G, Wozniak D, Price M, Sesma M (1991). "NMDA antagonist neurotoxicity: mechanism and prevention". Science 254 (5037): 1515–8. doi:10.1126/science.1835799. PMID 1835799. 
  21. ^ a b Farber, NB; Heinkel, C; Dribben, WH; Nemmers, B; Jiang, X (2004). "In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity". Brain research 1028 (1): 66–74. doi:10.1016/j.brainres.2004.08.065. PMID 15518643. 
  22. ^ Farber N, Hanslick J, Kirby C, McWilliams L, Olney J (1998). "Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity". Neuropsychopharmacology 18 (1): 57–62. doi:10.1016/S0893-133X(97)00127-9. PMID 9408919. 
  23. ^ a b Farber, NB; Jiang, X; Dikranian, K; Nemmers, B (2003). "Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions". Brain research 993 (1–2): 90–100. doi:10.1016/j.brainres.2003.09.002. PMID 14642834. 
  24. ^ Maas, AI (2001). "Neuroprotective agents in traumatic brain injury". Expert Opinion on Investigational Drugs 10 (4): 753–767. doi:10.1517/13543784.10.4.753. PMID 11281824. 
  25. ^ http://www.bluelight.ru/vb/archive/index.php/t-175748.html
  26. ^ Chen, HS; Lipton SA (2006). "The chemical biology of clinically tolerated NMDA receptor antagonists". Journal of Neurochemistry 97 (6): 1611–26. doi:10.1111/j.1471-4159.2006.03991.x. PMID 16805772. 
  27. ^ Gardoni, F; Di Luca M (2006). "New targets for pharmacological intervention in the glutamatergic synapse". European Journal of Pharmacology 545 (1): 2–10. doi:10.1016/j.ejphar.2006.06.022. PMID 16831414. 
  28. ^ Abizaid A, Liu Z, Andrews Z, Shanabrough M, Borok E, Elsworth J, Roth R, Sleeman M, Picciotto M, Tschöp M, Gao X, Horvath T (2006). "Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite". J Clin Invest 116 (12): 3229–39. doi:10.1172/JCI29867. PMC 1618869. PMID 17060947. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1618869. 
  29. ^ van den Bos R, Charria Ortiz G, Cools A (1992). "Injections of the NMDA-antagonist D-2-amino-7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enhance switching between cue-directed behaviours in a swimming test procedure". Behav Brain Res 48 (2): 165–70. doi:10.1016/S0166-4328(05)80153-6. PMID 1535501. 
  30. ^ Eblen F, Löschmann P, Wüllner U, Turski L, Klockgether T (1996). "Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions". Eur J Pharmacol 299 (1–3): 9–16. doi:10.1016/0014-2999(95)00795-4. PMID 8901001. 
  31. ^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
  32. ^ "MedlinePlus Drug Information: Amantadine." MedlinePlus website Accessed May 29, 2007
  33. ^ Wong BY, Coulter DA, Choi DW, Prince DA (1988). "Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices". Neurosci. Lett. 85 (2): 261–6. doi:10.1016/0304-3940(88)90362-X. PMID 2897648. 
  34. ^ Fix AS, Horn JW, Wightman KA, et al. (1993). "Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex". Exp. Neurol. 123 (2): 204–15. doi:10.1006/exnr.1993.1153. PMID 8405286. 
  35. ^ a b Controlled Substances Act. Accessed from the US Drug Enforcement Administration website on May 29, 2007.
  36. ^ Popik, P, Layer, RT, Skolnick, P (1994). "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex". Psychopharmacology (Berl) 114 (4): 672–4. doi:10.1007/BF02245000. PMID 7531855. 
  37. ^ Chawla, PS; Kochar MS (2006). "What's new in clinical pharmacology and therapeutics". WMJ 105 (3): 24–29. PMID 16749321. 
  38. ^ Grasshoff C, Drexler B, Rudolph U, Antkowiak B (2006). "Anaesthetic drugs: linking molecular actions to clinical effects". Curr. Pharm. Des. 12 (28): 3665–79. doi:10.2174/138161206778522038. PMID 17073666. 
  39. ^ Ko JC, Smith TA, Kuo WC, Nicklin CF (1998). "Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets". Journal of the American Animal Hospital Association 34 (5): 407–16. PMID 9728472. 
  40. ^ Nadler V, Mechoulam R, Sokolovsky M (November 1993). "The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain". Neurosci. Lett. 162 (1–2): 43–5. doi:10.1016/0304-3940(93)90555-Y. PMID 8121633. 
  41. ^ Muir, KW (2005). "Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists". Current Opinion in Pharmacology 6 (1): 53–60. doi:10.1016/j.coph.2005.12.002. PMID 16359918. 
  42. ^ Harrison N, Simmonds M (1985). "Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex". Br J Pharmacol 84 (2): 381–91. PMC 1987274. PMID 2858237. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1987274. 
  43. ^ Hartley DM, Monyer H, Colamarino SA, Choi DW (1990). "7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture". Eur J Neurosci 2 (4): 291–5. doi:10.1111/j.1460-9568.1990.tb00420.x. PMID 12106035. 
  44. ^ Frankiewicz T, Pilc A, Parsons C (2000). "Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices". Neuropharmacology 39 (4): 631–42. doi:10.1016/S0028-3908(99)00168-9. PMID 10728884. 
  45. ^ Khan MJ, Seidman MD, Quirk WS, Shivapuja BG (2000). "Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig". Eur Arch Otorhinolaryngol 257 (4): 177–81. doi:10.1007/s004050050218. PMID 10867830. 
  46. ^ Prous Science: Molecule of the Month January 2005

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