NMDA receptor antagonist

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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.

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[edit] Uses and effects

NMDA receptor antagonists are induce a state of called "dissociative anesthesia", which is marked by catalepsy, amnesia, and analgesia.[1] Ketamine and other NMDA receptor antagonists are most frequently used in conjunction with diazepam as anesthesia in cosmetic or reconstructive plastic surgery[2] and in the treatment of burn victims.[3] Ketamine is a favored anesthetic for emergency patients with unknown medical history because it depresses breathing less than other anesthetics.[4] The NMDA receptor antagonist dextromethorphan is one of the most commonly used cough supressants in the world.[5]

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.[6] Schizophrenia may also have to do with inadequate NMDA receptor function (the "glutamate hypothesis" of schizophrenia). [7] 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,[8] catatonia,[9] ataxia,[10] anaesthesia,[11] and learning and memory deficits.[12]

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.[13]

[edit] NMDA receptor antagonist neurotoxicity

Main article: Olney's lesions

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."[14][15] Several drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists, such as anticholinergics, diazepam, barbiturates,[16] ethanol,[17] 5-HT2A serotonin agonists,[18] and muscimol.[19]

[edit] 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[20] and studies have started to find agents that prevent this neurotoxicity.[19][17] 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.[21] This interference with normal function could be responsible for neuronal death that sometimes results from NMDA receptor antagonist use.[22]

[edit] Pharmacology of blockade

Simplified model of NMDAR activation and various types of NMDAR blockers. A: To open, an NMDAR must bind glutamate and glycine, and must not be bound by inhibitors that can cause the NMDAR to close by binding to allosteric sites. NMDAR antagonists fall into four categories: competitive antagonists (B), which bind to and block the glutamate binding site; glycine antagonists (C), which bind to and block the glycine site; noncompetitive antagonists (D), which inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists (E), which block the ion channel by binding to a site within it.
Simplified model of NMDAR activation and various types of NMDAR blockers. A: To open, an NMDAR must bind glutamate and glycine, and must not be bound by inhibitors that can cause the NMDAR to close by binding to allosteric sites. NMDAR antagonists fall into four categories: competitive antagonists (B), which bind to and block the glutamate binding site; glycine antagonists (C), which bind to and block the glycine site; noncompetitive antagonists (D), which inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists (E), which block the ion channel by binding to a site within it.[10]

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.

[edit] Examples

Uncompetitive channel blockers include:

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.[26] Approved in the U.S. by the Food and Drug Administration for the treatment of Alzheimer's disease.[27]
  • Remacimide. Principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.[28]

Glycine antagonists (drugs that act at the glycine binding site) include:

Competitive antagonists include:

  • AP7 (2-amino-7-phosphonoheptanoic acid)[31]
  • APV (R-2-amino-5-phosphonopentanoate)[32]
  • CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid)[33]

[edit] References

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  2. ^ Ersek R (2004). "Dissociative anesthesia for safety's sake: ketamine and diazepam--a 35-year personal experience". Plast Reconstr Surg 113 (7): 1955-9. PMID 15253183. 
  3. ^ Ceber M, Salihoglu T. "Ketamine may be the first choice for anesthesia in burn patients". J Burn Care Res 27 (5): 760-2. PMID 16998413. 
  4. ^ 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. PMID 17301376. 
  5. ^ 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. PMID 17154678. 
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  7. ^ 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. PMID 15759151. Retrieved on 2007-01-17. 
  8. ^ Muir, KW; Lees KR (1995). "Clinical experience with excitatory amino acid antagonist drugs". Stroke 26 (3): 503-513. Retrieved on 2007-01-17. 
  9. ^ Aarts, MM; Tymianski M (2003). "Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors". Biochemical Pharmacology 66 (6): 877-886. PMID 12963474. Retrieved on 2007-01-17. 
  10. ^ a b Kim AH, Kerchner GA, and Choi DW. (2002). "Blocking Excitotoxicity". In CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. Pages 3-36.
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  14. ^ Olney J, Labruyere J, Price M (1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360-2. PMID 2660263. 
  15. ^ Hargreaves R, Hill R, Iversen L. "Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology". Acta Neurochir Suppl (Wien) 60: 15-9. PMID 7976530. 
  16. ^ Olney J, Labruyere J, Wang G, Wozniak D, Price M, Sesma M (1991). "NMDA antagonist neurotoxicity: mechanism and prevention". Science 254 (5037): 1515-8. PMID 1835799. 
  17. ^ a b Farber, NB (2004). "In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity.". PMID 15518643. Retrieved on 2007-01-18. 
  18. ^ 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. PMID 9408919. 
  19. ^ a b Farber, NB (2003). "Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions.". PMID 14642834. Retrieved on 2007-01-18. 
  20. ^ Maas, AI (2001). "Neuroprotective agents in traumatic brain injury". Expert Opinion On Investigational Drugs 10 (4): 753-767. PMID 11281824. Retrieved on 2007-01-17. 
  21. ^ Chen, HS; Lipton SA. "The chemical biology of clinically tolerated NMDA receptor antagonists". Journal of Neurochemistry 97 (6): 1611-1126. PMID 16805772. Retrieved on 2007-01-17. 
  22. ^ Gardoni, F; Di Luca M (2006). "New targets for pharmacological intervention in the glutamatergic synapse". European Journal of Pharmacology 545 (1): 2-10. PMID 16831414. Retrieved on 2007-01-17. 
  23. ^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
  24. ^ 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. Abstract
  25. ^ 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. PMID 2858237. 
  26. ^ Robinson, DM; Keating GM (2006). "Memantine: a review of its use in Alzheimer's disease". Drugs 66 (11): 1515-1534. PMID 16906789. Retrieved on 2007-01-17. 
  27. ^ Chawla, PS; Kochar MS (2006). "What's new in clinical pharmacology and therapeutics". WMJ 105 (3): 24-29. PMID 16749321. Retrieved on 2007-01-17. 
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  31. ^ 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. PMID 1535501. 
  32. ^ 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. PMID 17060947. 
  33. ^ 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. PMID 8901001. 

[edit] See also

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