Chemistry:NMDA receptor antagonist

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Short description: Class of anesthetics
Ketamine, one of the most popular NMDA receptor antagonists.

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

Several synthetic opioids function additionally as NMDAR-antagonists, such as pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, and ketobemidone.

Some NMDA receptor antagonists, such as ketamine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N2O), are sometimes used as recreational drugs, 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.[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] Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world[4]), is known to be an NMDA receptor antagonist.

Numerous detrimental symptoms are linked to depressed NMDA receptor function. 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. 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] anesthesia,[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 inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug.[13]

Most NMDA receptor antagonists are metabolized in the liver.[14][15] Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.[16]

NMDA receptor antagonists are also under investigation as antidepressants. Ketamine has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019, esketamine, an NMDA antagonist enantiomer of ketamine, was approved for use as an antidepressant in the United States.[17] In 2022, Auvelity was approved by the FDA for the treatment of depression.[citation needed] This combination medication contains dextromethorphan, an NMDA receptor antagonist.

Neurotoxicity

Main page: Chemistry:Olney's lesions

Olney's lesions involve mass vacuolization of neurons observed in rodents.[18][19] 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.[20][21] A 2009 review found no evidence of ketamine-induced neuron death in humans.[22] However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not.[23] 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,[24] ethanol,[25] 5-HT2A serotonin receptor agonists,[26] anticonvulsants,[27] and muscimol.[28]

Potential for treatment of excess 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,[29] and studies have started to find agents that prevent this neurotoxicity.[25][28] 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.[30] Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal.[31]

Mechanism of action

Simplified model of NMDAR activation and various types of NMDAR blockers.[10]

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 blocks, binding to neurotransmitter glutamate sites; glycine antagonists blocks, binding to glycine sites; noncompetitive antagonists inhibits, binding to NMDARs allosteric sites; and uncompetitive antagonists blocks, binding to a site within the ion channel.[10]

Examples

Competitive antagonists

  • AP5 (APV, R-2-amino-5-phosphonopentanoate).[32]
  • AP7 (2-amino-7-phosphonoheptanoic acid).[33]
  • CGP-37849[34]
  • CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid).[35]
  • Selfotel: an anxiolytic, 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.[50]
  • Huperzine A.[51][52][53]
  • Dipeptide D-Phe-L-Tyr.[54] weakly inhibit NMDA/Gly-induced currents possibly by ifenprodil-like mechanism.
  • Ibogaine: a naturally-occurring alkaloid found in plants of the family Apocynaceae. Has been used, albeit with limited evidence, to treat opioid and other addictions.[55][56]
  • Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.[57]
  • Rhynchophylline an alkaloid, found in Kratom and Rubiaceae.
  • Gabapentin: a calcium α2δ ligand that is commonly used in diabetic neuropathy.[58]

Glycine antagonists

These drugs act at the glycine binding site:


Potencies

Uncompetitive channel blockers

Against rat NMDAR[66]
Compound IC50 (nM) Ki (nM)
(+)-MK-801 4.1 2.5
Chlorophenidine 14.6 9.3
Diphenidine 28.6 18.2
Methoxyphenidine 56.5 36.0
Phencyclidine 91 57.9
Ketamine 508.5 323.9
Memantine 594.2 378.4

See also

References

  1. ↑ "Dissociative anesthesia". JAMA 215 (7): 1126–30. February 1971. doi:10.1001/jama.1971.03180200050011. PMID 5107596. 
  2. ↑ "Ketamine may be the first choice for anesthesia in burn patients". Journal of Burn Care & Research 27 (5): 760–2. 2006. doi:10.1097/01.BCR.0000238091.41737.7C. PMID 16998413. 
  3. ↑ "Use of ketamine in severe status asthmaticus in intensive care unit". Iranian Journal of Allergy, Asthma, and Immunology 2 (4): 175–80. December 2003. PMID 17301376. 
  4. ↑ "Comparative efficacy and tolerability of pholcodine and dextromethorphan in the management of patients with acute, non-productive cough : a randomized, double-blind, multicenter study". Treatments in Respiratory Medicine 5 (6): 509–13. 2006. doi:10.2165/00151829-200605060-00014. PMID 17154678. 
  5. ↑ "NMDA receptor regulation of memory and behavior in humans". Hippocampus 11 (5): 529–42. 2001. doi:10.1002/hipo.1069. PMID 11732706. 
  6. ↑ "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. April 2005. doi:10.1007/s00213-005-2210-x. PMID 15759151. 
  7. ↑ "The kynurenic acid hypothesis of schizophrenia". Physiology & Behavior 92 (1–2): 203–9. September 2007. doi:10.1016/j.physbeh.2007.05.025. PMID 17573079. 
  8. ↑ "Clinical experience with excitatory amino acid antagonist drugs". Stroke 26 (3): 503–13. March 1995. doi:10.1161/01.STR.26.3.503. PMID 7886734. http://stroke.ahajournals.org/cgi/content/full/26/3/503. 
  9. ↑ "Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors". Biochemical Pharmacology 66 (6): 877–86. September 2003. doi:10.1016/S0006-2952(03)00297-1. PMID 12963474. 
  10. ↑ 10.0 10.1 10.2 "Blocking Excitotoxicity". CNS Neuroprotection. New York: Springer. 2002. pp. 3–36. 
  11. ↑ "The NMDA-receptor antagonist CPP abolishes neurogenic 'wind-up pain' after intrathecal administration in humans". Pain 51 (2): 249–53. November 1992. doi:10.1016/0304-3959(92)90266-E. PMID 1484720. 
  12. ↑ "Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans". Psychopharmacology 124 (3): 261–6. April 1996. doi:10.1007/BF02246666. PMID 8740048. 
  13. ↑ "Ketamine associated psychedelic effects and dependence". Singapore Medical Journal 44 (1): 31–4. January 2003. PMID 12762561. 
  14. ↑ "The preoperative administration of intravenous dextromethorphan reduces postoperative morphine consumption". Anesthesia and Analgesia 89 (3): 748–52. September 1999. doi:10.1097/00000539-199909000-00041. PMID 10475318. 
  15. ↑ "Metabolism of ketamine stereoisomers by human liver microsomes". Anesthesiology 77 (6): 1201–7. December 1992. doi:10.1097/00000542-199212000-00022. PMID 1466470. 
  16. ↑ "The development of tolerance to ketamine in rats and the significance of hepatic metabolism". British Journal of Pharmacology 64 (1): 63–9. September 1978. doi:10.1111/j.1476-5381.1978.tb08641.x. PMID 698482. 
  17. ↑ "FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic". 24 March 2020. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm. 
  18. ↑ "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. June 1989. doi:10.1126/science.2660263. PMID 2660263. Bibcode: 1989Sci...244.1360O. 
  19. ↑ "Neuroprotective NMDA Antagonists: The Controversy over Their Potential for Adverse Effects on Cortical Neuronal Morphology". Brain Edema IX. 60. 1994. 15–9. doi:10.1007/978-3-7091-9334-1_4. ISBN 978-3-7091-9336-5. 
  20. ↑ "Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys". Addiction Biology 19 (2): 185–94. March 2014. doi:10.1111/adb.12004. PMID 23145560. 
  21. ↑ "Ketamine-induced neuronal cell death in the perinatal rhesus monkey". Toxicological Sciences 98 (1): 145–58. July 2007. doi:10.1093/toxsci/kfm084. PMID 17426105. 
  22. ↑ "Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine". Annals of Emergency Medicine 54 (2): 181–90. August 2009. doi:10.1016/j.annemergmed.2008.10.003. PMID 18990467. 
  23. ↑ "Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study". Addiction 105 (1): 121–33. January 2010. doi:10.1111/j.1360-0443.2009.02761.x. PMID 19919593. 
  24. ↑ "NMDA antagonist neurotoxicity: mechanism and prevention". Science 254 (5037): 1515–8. December 1991. doi:10.1126/science.1835799. PMID 1835799. Bibcode: 1991Sci...254.1515O. 
  25. ↑ 25.0 25.1 "In the adult CNS, ethanol prevents rather than produces NMDA antagonist-induced neurotoxicity". Brain Research 1028 (1): 66–74. November 2004. doi:10.1016/j.brainres.2004.08.065. PMID 15518643. 
  26. ↑ "Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity". Neuropsychopharmacology 18 (1): 57–62. January 1998. doi:10.1016/S0893-133X(97)00127-9. PMID 9408919. 
  27. ↑ "Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity". Molecular Psychiatry 7 (1): 726–733. 23 August 2002. doi:10.1038/sj.mp.4001087. PMID 12192617. 
  28. ↑ 28.0 28.1 "Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions". Brain Research 993 (1–2): 90–100. December 2003. doi:10.1016/j.brainres.2003.09.002. PMID 14642834. 
  29. ↑ "Neuroprotective agents in traumatic brain injury". Expert Opinion on Investigational Drugs 10 (4): 753–67. April 2001. doi:10.1517/13543784.10.4.753. PMID 11281824. 
  30. ↑ "The chemical biology of clinically tolerated NMDA receptor antagonists". Journal of Neurochemistry 97 (6): 1611–26. June 2006. doi:10.1111/j.1471-4159.2006.03991.x. PMID 16805772. 
  31. ↑ "New targets for pharmacological intervention in the glutamatergic synapse". European Journal of Pharmacology 545 (1): 2–10. September 2006. doi:10.1016/j.ejphar.2006.06.022. PMID 16831414. 
  32. ↑ "Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite". The Journal of Clinical Investigation 116 (12): 3229–39. December 2006. doi:10.1172/JCI29867. PMID 17060947. 
  33. ↑ "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". Behavioural Brain Research 48 (2): 165–70. June 1992. doi:10.1016/S0166-4328(05)80153-6. PMID 1535501. 
  34. ↑ "CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity". British Journal of Pharmacology 99 (4): 791–7. April 1990. doi:10.1111/j.1476-5381.1990.tb13008.x. PMID 1972895. 
  35. ↑ "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". European Journal of Pharmacology 299 (1–3): 9–16. March 1996. doi:10.1016/0014-2999(95)00795-4. PMID 8901001. 
  36. ↑ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
  37. ↑ "MedlinePlus Drug Information: Amantadine." MedlinePlus website Accessed 29 May 2007
  38. ↑ "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations". British Journal of Pharmacology 160 (2): 283–91. May 2010. doi:10.1111/j.1476-5381.2010.00707.x. PMID 20423340. 
  39. ↑ 39.0 39.1 "Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices". Neuroscience Letters 85 (2): 261–6. February 1988. doi:10.1016/0304-3940(88)90362-X. PMID 2897648. 
  40. ↑ European Patent 0346791 1,2-Diarylethylamines for Treatment of Neurotoxic Injury.
  41. ↑ "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". Experimental Neurology 123 (2): 204–15. October 1993. doi:10.1006/exnr.1993.1153. PMID 8405286. 
  42. ↑ Maxwell, Kenneth S.; Robinson, James M.; Hoffmann, Ines; Hou, Huiying J.; Searchfield, Grant; Baguley, David M.; McMurry, Gordon; Piu, Fabrice et al. (October 8, 2021). "Intratympanic Administration of OTO-313 Reduces Tinnitus in Patients With Moderate to Severe, Persistent Tinnitus: A Phase 1/2 Study". Otology & Neurotology (Ovid Technologies (Wolters Kluwer Health)) 42 (10): e1625–e1633. doi:10.1097/mao.0000000000003369. ISSN 1531-7129. PMID 34629442. 
  43. ↑ "Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex". British Journal of Pharmacology 84 (2): 381–91. February 1985. doi:10.1111/j.1476-5381.1985.tb12922.x. PMID 2858237. 
  44. ↑ "What's new in clinical pharmacology and therapeutics". WMJ 105 (3): 24–9. May 2006. PMID 16749321. 
  45. ↑ "Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury". Neural Regeneration Research 12 (5): 702–713. May 2017. doi:10.4103/1673-5374.206633. PMID 28616020. 
  46. ↑ "Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss". Proceedings of the National Academy of Sciences of the United States of America 110 (27): E2518–27. July 2013. doi:10.1073/pnas.1306832110. PMID 23776240. Bibcode: 2013PNAS..110E2518T. 
  47. ↑ "Anaesthetic drugs: linking molecular actions to clinical effects". Current Pharmaceutical Design 12 (28): 3665–79. 2006. doi:10.2174/138161206778522038. PMID 17073666. 
  48. ↑ "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. 1998. doi:10.5326/15473317-34-5-407. PMID 9728472. 
  49. ↑ "Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists". Bioorganic & Medicinal Chemistry 18 (22): 7855–67. November 2010. doi:10.1016/j.bmc.2010.09.047. PMID 20965735. 
  50. ↑ "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". Neuroscience Letters 162 (1–2): 43–5. November 1993. doi:10.1016/0304-3940(93)90555-Y. PMID 8121633. 
  51. ↑ "Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons". Neuroscience 105 (3): 663–9. 2001. doi:10.1016/s0306-4522(01)00206-8. PMID 11516831. 
  52. ↑ "Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease?". Frontiers in Aging Neuroscience 6: 216. 2014. doi:10.3389/fnagi.2014.00216. PMID 25191267. 
  53. ↑ "[+-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats"]. Chemico-Biological Interactions 175 (1–3): 387–95. September 2008. doi:10.1016/j.cbi.2008.05.023. PMID 18588864. https://zenodo.org/record/1258822. 
  54. ↑ "Short peptide with an inhibitory activity on the NMDA/Gly-induced currents". SAR and QSAR in Environmental Research 30 (9): 683–695. 2019. doi:10.1080/1062936X.2019.1653965. 
  55. ↑ "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3HMK-801 binding to the NMDA receptor complex"]. Psychopharmacology 114 (4): 672–4. May 1994. doi:10.1007/BF02245000. PMID 7531855. https://zenodo.org/record/1232548. 
  56. ↑ "Ibogaine in the treatment of substance dependence". Current Drug Abuse Reviews 6 (1): 3–16. March 2013. doi:10.2174/15672050113109990001. PMID 23627782. 
  57. ↑ "Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists". Current Opinion in Pharmacology 6 (1): 53–60. February 2006. doi:10.1016/j.coph.2005.12.002. PMID 16359918. 
  58. ↑ "Inhibitory effect of gabapentin on N-methyl-D-aspartate receptors expressed in Xenopus oocytes". Acta Anaesthesiologica Scandinavica 51 (1): 122–8. January 2007. doi:10.1111/j.1399-6576.2006.01183.x. PMID 17073851. 
  59. ↑ "7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture". The European Journal of Neuroscience 2 (4): 291–295. 1990. doi:10.1111/j.1460-9568.1990.tb00420.x. PMID 12106035. 
  60. ↑ "Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices". Neuropharmacology 39 (4): 631–42. February 2000. doi:10.1016/S0028-3908(99)00168-9. PMID 10728884. 
  61. ↑ "Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig". European Archives of Oto-Rhino-Laryngology 257 (4): 177–81. 2000. doi:10.1007/s004050050218. PMID 10867830. 
  62. ↑ "Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site". The Journal of Biological Chemistry 288 (46): 33124–35. November 2013. doi:10.1074/jbc.M113.480210. PMID 24072709. 
  63. ↑ "Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria". Molecular Psychiatry 7 (4): 359–67. 2002. doi:10.1038/sj.mp.4000976. PMID 11986979. 
  64. ↑ "Long-term changes in glutamatergic synaptic transmission in phenylketonuria". Brain 128 (Pt 2): 300–7. February 2005. doi:10.1093/brain/awh354. PMID 15634735. 
  65. ↑ "Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia". Anesthesiology 112 (3): 614–22. March 2010. doi:10.1097/ALN.0b013e3181cea398. PMID 20124979. 
  66. ↑ "Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues". PLOS ONE 11 (6): e0157021. 2016. doi:10.1371/journal.pone.0157021. PMID 27314670. Bibcode: 2016PLoSO..1157021W. 



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