Dizocilpine

Dizocilpine
Clinical data
Routes of
administration		By mouth, IM
ATC code
  • None
Identifiers
  • (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H15N
Molar mass221.303 g·mol−1
3D model (JSmol)
Melting point68.75 °C (155.75 °F)
  • C[C@]1(C2=C(C[C@H]3N1)C=CC=C2)C4=C3C=CC=C4
  • InChI=1S/C16H15N/c1-16-13-8-4-2-6-11(13)10-15(17-16)12-7-3-5-9-14(12)16/h2-9,15,17H,10H2,1H3/t15-,16+/m1/s1 checkY
  • Key:LBOJYSIDWZQNJS-CVEARBPZSA-N checkY
 X markNcheckY (what is this?)  (verify)

Dizocilpine (INN), also known as MK-801, is a pore blocker of the NMDA receptor, discovered by a team at Merck in 1982. The drug acts as a potent anticonvulsant and dissociative agent, but is not used clinically due to an adverse safety profile. In laboratory rats, the drug induces Olney's lesions. Dizocilpine is also associated with a number of adverse psychological reactions, including cognitive disruption and psychotic-spectrum reactions. By inhibiting long-term potentiation, dizocilpine impairs learning and memory in rodent and primate models. Due to safety issues, dizocilpine remains a tool in scientific research, rather than a clinical medicine.

Dizocilpine also has activity at nicotinic acetylcholine receptors, as well as serotonin and dopamine transporters.

Toxicity

Olney's lesions

Dizocilpine, along with various other NMDA antagonists, induce the formation of brain lesions first discovered by John W. Olney in 1989. Dizocilpine leads to the development of neuronal vacuolization in the posterior cingulate/retrosplenial cortex. Other neurons in the area expressed an abnormal amount of heat shock protein as well as increased glucose metabolism in response to NMDA antagonist exposure. Vacuoles began to form within 30 minutes of a subcutaneous dose of dizocilpine 1 mg/kg. Neurons in this area necrotized and were accompanied by a glial response involving astrocytes and microglia.

Pharmacology

Pharmacodynamics

Dizocilpine binds to the PCP1 site at NMDA receptors, physically blocking the pore, preventing an intracellular influx of positively charged ions, such as calcium (Ca2+) and sodium (Na+). Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it.

Dizocilpine has also been found to act as a nicotinic acetylcholine receptor antagonist. It has been shown to bind to and inhibit the serotonin and dopamine transporters as well.

Recreational use

Dizocilpine is rarely used recreationally due to severe risks, unclear dosage information, and lesser recreational benefit compared to other NMDA antagonists. In a study testing self-administration habits of rats with PCP, CPP, and dizocilpine, it was found that the rats showed similar self-administration behavior for all three of the drugs. When a dopamine antagonist was also administered, self administration did not decrease, indicating that dizocilpine has reward potential beyond dopaminergic effects. In another study, dizocilpine administration elicited a strong conditioned place preference in animals, demonstrating a level of reinforcement.

Research

An animal model of schizophrenia

Dizocilpine has been used to create animal models of schizophrenia due to its ability to induce several positive and negative symptoms, serving as a tool in the evaluation of the glutamatergic hypothesis of the disorder.

The NMDA receptor blockade imposed by dizocilpine accurately models schizophrenia in multiple areas. While low doses were shown to primarily impair cognitive processes such as working memory and long-term potentiation, increased doses led to stereotypy and hyperlocomotion, which correspond to positive symptoms. However, motor and sensorimotor levels influence memory performance, meaning that these additional disruptions may mask or confound certain memory impairments. Subchronic exposure has been shown to mimic psychosis, while chronic administration in laboratory animals resulted in neuropathological changes resembling those in schizophrenia.

Dizocilpine shows selectivity for parvalbumin-positive (PV+) GABAergic interneurons in the prefrontal cortex. Due to downregulation of NMDA receptors on these inhibitory neurons, GABA output is reduced. This leads to paradoxical hyper-excitation of cortical pyramidal neurons, disrupting cognitive processing.

Investigational applications

The early development of dizocilpine was centered around its potential as a neuroprotective agent that could potentially be used to mitigate excitotoxicity caused by stroke, brain injury, and various neurodegenerative conditions. However, development was dropped as psychotomimetic effects and toxicity such as Olney's lesions became apparent, leaving it as a tool for research into NMDA antagonism and psychosis rather than a clinical drug.

The administration of dizocilpine was shown to protect the hippocampus from ischemia-induced neurodegeneration in the gerbil. During ischemic events, blood and oxygen deprivation causes the brain to release large amounts of excitatory neurotransmitters, leading to excitotoxicity. By blocking NMDA receptors, dizocilpine prevents excessive intracellular calcium influx, preventing excitotoxicity.

See also

References

  1. ↑ US Patent 4399141, Anderson P, Christy ME, Evans BE, "5-Alkyl or hydroxyalkyl substituted-10,11-imines & Anticonvulsant Use Thereof", published 1983-08-16, issued 1983-08-16, assigned to Merck & Company Inc
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  5. ↑ Murray TK, Ridley RM, Snape MF, Cross AJ (August 1995). "The effect of dizocilpine (MK-801) on spatial and visual discrimination tasks in the rat". Behavioural Pharmacology. 6 (5 And 6): 540–549. doi:10.1097/00008877-199508000-00014. PMID 11224361. S2CID 29029744.
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  13. 1 2 Olney JW, Labruyere J, Price MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science. 244 (4910). New York, N.Y.: 1360–1362. Bibcode:1989Sci...244.1360O. doi:10.1126/science.2660263. PMID 2660263.
  14. ↑ Sharp FR, Jasper P, Hall J, Noble L, Sagar SM (December 1991). "MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex". Annals of Neurology. 30 (6): 801–809. doi:10.1002/ana.410300609. PMID 1838680. S2CID 19052517.
  15. ↑ Hargreaves RJ, Rigby M, Smith D, Hill RG, Iversen LL (December 1993). "Competitive as well as uncompetitive N-methyl-D-aspartate receptor antagonists affect cortical neuronal morphology and cerebral glucose metabolism". Neurochemical Research. 18 (12): 1263–1269. doi:10.1007/BF00975046. PMID 7903796. S2CID 20604534.
  16. ↑ Fix AS, Horn JW, Truex LL, Smith RA, Gomez E (1994). "Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate)". Acta Neuropathologica. 88 (6): 511–519. doi:10.1007/BF00296487. PMID 7879597. S2CID 28368130.
  17. ↑ Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, et al. (October 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". Experimental Neurology. 123 (2): 204–215. doi:10.1006/exnr.1993.1153. PMID 8405286. S2CID 24839154.
  18. ↑ Huettner JE, Bean BP (February 1988). "Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels". Proceedings of the National Academy of Sciences of the United States of America. 85 (4): 1307–1311. Bibcode:1988PNAS...85.1307H. doi:10.1073/pnas.85.4.1307. PMC 279756. PMID 2448800.
  19. ↑ Clarke PB, Reuben M (January 1995). "Inhibition by dizocilpine (MK-801) of striatal dopamine release induced by MPTP and MPP+: possible action at the dopamine transporter". British Journal of Pharmacology. 114 (2): 315–322. doi:10.1111/j.1476-5381.1995.tb13229.x. PMC 1510234. PMID 7881731.
  20. ↑ Carlezon WA, Wise RA (May 1996). "Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex". The Journal of Neuroscience. 16 (9): 3112–3122. doi:10.1523/JNEUROSCI.16-09-03112.1996. PMC 6579051. PMID 8622141.
  21. ↑ Papp M, Moryl E, Maccecchini ML (December 1996). "Differential effects of agents acting at various sites of the NMDA receptor complex in a place preference conditioning model". European Journal of Pharmacology. 317 (2–3): 191–196. doi:10.1016/S0014-2999(96)00747-9. PMID 8997600.
  22. ↑ Moghaddam B, Javitt D (January 2012). "From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment". Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 37 (1): 4–15. doi:10.1038/npp.2011.181. PMC 3238069. PMID 21956446.
  23. ↑ Liu W, Wang D, Hong W, Yu Y, Tang J, Wang J, et al. (March 2017). "Psychotomimetic effects of different doses of MK-801 and the underlying mechanisms in a selective memory impairment model". Behavioural Brain Research. 320: 517–525. doi:10.1016/j.bbr.2016.10.011. PMID 27725171. Archived from the original on 2024-04-24.
  24. ↑ Braun I, Genius J, Grunze H, Bender A, Möller HJ, Rujescu D (December 2007). "Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism". Schizophrenia Research. 97 (1–3): 254–263. doi:10.1016/j.schres.2007.05.005. PMID 17601703. S2CID 22688722.
  25. ↑ Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (September 1986). "The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist". Proceedings of the National Academy of Sciences of the United States of America. 83 (18): 7104–7108. doi:10.1073/pnas.83.18.7104. PMC 386661. PMID 3529096.
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  28. ↑ Gill R, Foster AC, Woodruff GN (October 1987). "Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil". The Journal of Neuroscience. 7 (10): 3343–3349. doi:10.1523/JNEUROSCI.07-10-03343.1987. PMC 6569187. PMID 3312511.

Further reading