Dizocilpine

Dizocilpine
Systematic (IUPAC) name
[5R,10S]-[+]-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
Clinical data
Routes of
administration		 Oral, IM
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Biological half-life ?
Excretion ?
Identifiers
CAS Number 77086-21-6 N
PubChem CID 180081
IUPHAR/BPS 2403
DrugBank ? N
ChemSpider 156718 YesY
UNII 7PY8KH681I YesY
ChEMBL CHEMBL284237 YesY
Chemical data
Formula C16H15N
Molar mass 221.297 g/mol
Physical data
Melting point 68.75 °C (155.75 °F)
 NYesY (what is this?)  (verify)

Dizocilpine (INN), also known as MK-801, is an uncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982.[1] Glutamate is the brain's primary excitatory neurotransmitter. The channel is normally blocked with a magnesium ion and requires depolarization of the neuron to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization.[2] Dizocilpine binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including an influx of calcium (Ca2+), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it.[3] The drug acts as a potent anti-convulsant and likely has dissociative anesthetic properties, but it is not used clinically for this purpose due to the discovery of brain lesions, called Olney's lesions (see below), in test rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It also inhibited the induction of long term potentiation.[4] Instead, the NMDA receptor pore-blocker ketamine is used as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary psychosis in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used non-competitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.

Dizocilpine has also been found to act as a nicotinic acetylcholine receptor antagonist.[5][6][7] It has been shown to bind to and inhibit the serotonin and dopamine transporters as well.[8][9]

An animal model of schizophrenia

Dizocilpine has a great deal of potential to be used in research in creating animal models of schizophrenia. Unlike dopaminergic agonists, which mimic only the positive symptoms of schizophrenia, a single injection of dizocilpine was successful in modelling both the positive and negative symptoms of schizophrenia.[10] Another study found that, although repeated low doses of dizocilpine were only successful in mimicking behavioral changes such as a slight hyperlocomotion and decreased prepulse inhibition, repeated administration of a higher dose mimicked both the above changes as well as the neurochemical alterations found in first-episode schizophrenic patients.[11] Not only has temporary use been shown to mimic psychosis but chronic administration in laboratory animals resulted in similar neuropathological changes as in schizophrenia.[12]

Possible future medical uses

The effects of dizocilpine at NMDA receptors are clear and significant. NMDA receptors are key in the progression of excitotoxicity (a process in which an excessive amount of extracellular glutamate overexcites glutamate receptors and harms neurons). Thus NMDA receptor antagonists including dizocilpine have been extensively studied for use in treatment of diseases with excitotoxic components, such as stroke, traumatic brain injury, and neurodegenerative diseases such as Huntington's, Alzheimer's, and amyotrophic lateral sclerosis. Dizocilpine has shown effectiveness in protecting neurons in cell culture and animal models of excitotoxic neurodegeneration.[13][14][15] The administration of dizocilpine protected the hippocampus from ischemia-induced neurodegeneration in the gerbil. The ED50 (effective dose 50) for neuroprotection was 0.3 mg/kg and the majority of the animals were protected against the ischemia-induced damage at doses greater than or equal to 3 mg/kg, when dizocilpine was given one hour prior to the occlusion of the carotid arteries, although other studies have shown protection up to 24 hours post-insult. Excitatory amino acids, such as glutamate and aspartate, are released in toxic amounts when the brain is deprived of blood and oxygen and NMDA receptors are thought to prevent the neurodegeneration through the inhibition of these receptors.[16][17]

Behavioural studies have shown that NMDA receptors are involved in the development of psychological dependence caused by chronic administration of morphine. Dizocilpine suppressed the morphine-induced rewarding effect. It is suggested that stimulating NR2B subunits of the NMDA receptor and its associated kinases in the nucleus accumbens leads to the rewarding effect caused by morphine. Inhibition of this receptor and its kinases in the nucleus accumbens by co-treatment with NMDA antagonists prevents morphine-associated psychological dependence.[18] An earlier study has shown that the prevention of morphine-associated psychological dependence was not due to state-dependency effects induced by dizocilpine[19] but rather reflect the impairment of learning that is caused by NMDA antagonists.[20] This is consistent with studies showing that dizocilpine potentiates the addictive potential of morphine and other drugs (see below).

3-D molecular model

As an antidepressant, positive results were found in animal models of depression.[21] NMDA antagonists like dizocilpine have been shown in animal models to attenuate the hearing loss caused by aminoglycosides It is thought that aminoglycosides mimic endogenous polyamines at NMDA receptors and produce excitotoxic damage, leading to hair cell loss. Antagonizing NMDA receptors to reduce the excitotoxicity would prevent that hearing loss.[22][23] Dizocilpine was found to block the development of kindled seizures, although it does not have any effect on completed kindled seizures.[24] Oddly, it was discovered to decrease rabies virus production and is believed to be the first neurotransmitter antagonist to present with antiviral activity. Rat cortical neuron cells were infected with the rabies virus and those incubated with dizocilpine had virus produced reduced about 1000-fold. It is not known how MK-801 has this effect; the rabies virus suspension, without cells, was inoculated with dizocilpine and the drug failed to produce a virucidal effect, indicated that the mechanism of action is something other than direct killing of the virus. It was also tested against herpes simplex, vesicular stomatitis, poliovirus type I, and human immunodeficiency virus. It did not have activity against these other viruses, however.[25] Dizocilpine was also shown to potentiate the ability of levodopa to ameliorate akinesia and muscular rigidity in a rodent model of parkinsonism.[26] When dizocilpine was administered to rats 15 minutes after a spinal trauma, the long-term neurological recovery of the trauma was improved.[27] However, NMDA antagonists like dizocilpine have largely failed to show safety in clinical trials, possibly due to inhibition of NMDA receptor function that is necessary for normal neuronal function. Since dizocilpine is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have psychotomimetic side effects (such as hallucinations) that result from NMDA receptor blockade. Dizocilpine had a promising future as a neuroprotective agent until neurotoxic-like effects, called Olney's Lesions, were seen in certain brain regions of test rats.[28][29] Merck, a drug company, promptly dropped development of dizocilpine.

Olney's lesions

Main article: Olney's lesions

Dizocilpine, along with 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.[28] Other neurons in the area expressed an abnormal amount of heat shock protein[30] as well as increased glucose metabolism[31] in response to NMDA antagonist exposure. Vacuoles began to form within 30 minutes of a subcutaneous dose of dizocilpine 1 mg/kg.[32] Neurons in this area necrotized and were accompanied by a glial response involving astrocytes and microglia.[33]

However, it may be necessary to point out that Ketamine was also found in animal models to produce Olney's Lesions, but not in humans.

Recreational use

Dizocilpine may be effective as a recreational drug, and may have an active dose in the 50-100 μg range. Little is known in this context about its effects, dosage, and risks. The high potency of dizocilpine makes its dosage more difficult to accurately control when compared to other similar drugs. As a result, the chances of overdosing are high. Users tend to report that the experience is not as enjoyable as other dissociative drugs, and it is often accompanied by strong auditory hallucinations. Also, dizocilpine is much longer-lasting than similar dissociative drugs such as ketamine and phencyclidine (PCP), and causes far worse amnesia and residual deficits in thinking, which have hindered its acceptance as a recreational drug. Several animal studies have demonstrated the addictive potential of dizocilpine. Rats learned to lever-press in order to obtain injections of dizocilpine into the nucleus accumbens and frontal cortex, however, when given a dopamine antagonist at the same time, the lever-pressing was not altered, which shows that the rewarding effect of dizocilpine is not dependent on dopamine.[34] Intraperitoneal administration of dizocilpine also produced an enhancement in self-stimulation responding.[35] Rhesus monkeys were trained to self-administer cocaine or phencyclidine, then were offered dizocilpine instead. None of the four monkeys who were used to cocaine chose to self-administer dizocilpine but three out of the four monkeys who had been using phencyclidine self-administered dizocilpine, suggesting again that dizocilpine has potential as a recreational drug for those seeking a dissociative anaesthetic type of experience.[36] It was found that dizocilpine administration elicited conditioned place preference in animals, again demonstrating its reinforcing properties.[37][38]

A multiple drug fatality involving dizocilpine, benzodiazepines, and alcohol has been reported.[39]

Synthesis

Dizocilpine is made from dibenzosuberenone starting material.[40]

Dizocilpine synthesis: U.S. Patent 4,477,668 Dean R. Bender, Sandor Karady, Theresa Rothauser. Merck & Co., Inc.

See also

References

  1. ↑ US Patent 4399141, ANDERSON, P.; CHRISTY, M. E.; EVANS, B. E. , "5-Alkyl or hydroxyalkyl substituted-10,11-imines & Anticonvulsant Use Thereof", issued 1983-08-16, assigned to MERCK & CO INC
  2. ↑ Foster AC, Fagg GE (1987). "Neurobiology. Taking apart NMDA receptors". Nature 329 (6138): 395–6. doi:10.1038/329395a0. PMID 2443852.
  3. ↑ Huettner, James E; Bean, Bruce P (October 16, 1987). "Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels" (PDF). PNAS 85: 1307–1311. doi:10.1073/pnas.85.4.1307. Retrieved 2014-07-23.
  4. ↑ Coan EJ, Saywood W, Collingridge GL (September 1987). "MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices". Neurosci. Lett. 80 (1): 111–4. doi:10.1016/0304-3940(87)90505-2. PMID 2821457.
  5. ↑ Ramoa AS, Alkondon M, Aracava Y; et al. (July 1990). "The anticonvulsant MK-801 interacts with peripheral and central nicotinic acetylcholine receptor ion channels". The Journal of Pharmacology and Experimental Therapeutics 254 (1): 71–82. PMID 1694895.
  6. ↑ Amador M, Dani JA (March 1991). "MK-801 inhibition of nicotinic acetylcholine receptor channels". Synapse 7 (3): 207–15. doi:10.1002/syn.890070305. PMID 1715611.
  7. ↑ Briggs CA, McKenna DG (April 1996). "Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor". Neuropharmacology 35 (4): 407–14. doi:10.1016/0028-3908(96)00006-8. PMID 8793902.
  8. ↑ Iravani MM, Muscat R, Kruk ZL (June 1999). "MK-801 interaction with the 5-HT transporter: a real-time study in brain slices using fast cyclic voltammetry". Synapse 32 (3): 212–24. doi:10.1002/(SICI)1098-2396(19990601)32:3<212::AID-SYN7>3.0.CO;2-M. PMID 10340631.
  9. ↑ 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): 315–22. doi:10.1111/j.1476-5381.1995.tb13229.x. PMC 1510234. PMID 7881731.
  10. ↑ Rung JP, Carlsson A, Rydén Markinhuhta K, Carlsson ML (June 2005). "(+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia". Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (5): 827–32. doi:10.1016/j.pnpbp.2005.03.004. PMID 15916843.
  11. ↑ Eyjolfsson EM, Brenner E, Kondziella D, Sonnewald U (2006). "Repeated injection of MK801: an animal model of schizophrenia?". Neurochem. Int. 48 (6–7): 541–6. doi:10.1016/j.neuint.2005.11.019. PMID 16517016.
  12. ↑ 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". Schizophr. Res. 97 (1–3): 254–63. doi:10.1016/j.schres.2007.05.005. PMID 17601703.
  13. ↑ Ayala GX, Tapia R (December 2005). "Late N-methyl-D-aspartate receptor blockade rescues hippocampal neurons from excitotoxic stress and death after 4-aminopyridine-induced epilepsy". Eur. J. Neurosci. 22 (12): 3067–76. doi:10.1111/j.1460-9568.2005.04509.x. PMID 16367773.
  14. ↑ Kocaeli H, Korfali E, Oztürk H, Kahveci N, Yilmazlar S (2005). "MK-801 improves neurological and histological outcomes after spinal cord ischemia induced by transient aortic cross-clipping in rats". Surg Neurol 64 (Suppl 2): S22–6; discussion S27. doi:10.1016/j.surneu.2005.07.034. PMID 16256835.
  15. ↑ Mukhin AG, Ivanova SA, Knoblach SM, Faden AI (September 1997). "New in vitro model of traumatic neuronal injury: evaluation of secondary injury and glutamate receptor-mediated neurotoxicity". J. Neurotrauma 14 (9): 651–63. doi:10.1089/neu.1997.14.651. PMID 9337127.
  16. ↑ Barnes DM (February 1987). "Drug may protect brains of heart attack victims". Science 235 (4789): 632–3. doi:10.1126/science.3027893. PMID 3027893.
  17. ↑ Gill R, Foster AC, Woodruff GN (October 1987). "Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil". J. Neurosci. 7 (10): 3343–9. PMID 3312511.
  18. ↑ Narita M, Kato H, Miyoshi K, Aoki T, Yajima Y, Suzuki T (September 2005). "Treatment for psychological dependence on morphine: usefulness of inhibiting NMDA receptor and its associated protein kinase in the nucleus accumbens". Life Sci. 77 (18): 2207–20. doi:10.1016/j.lfs.2005.04.015. PMID 15946694.
  19. ↑ Tzschentke TM, Schmidt WJ (March 1997). "Interactions of MK-801 and GYKI 52466 with morphine and amphetamine in place preference conditioning and behavioural sensitization". Behav. Brain Res. 84 (1–2): 99–107. doi:10.1016/S0166-4328(97)83329-3. PMID 9079776.
  20. ↑ Morris RG, Anderson E, Lynch GS, Baudry M (1986). "Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5". Nature 319 (6056): 774–6. doi:10.1038/319774a0. PMID 2869411.
  21. ↑ Berk M (2000). "Depression therapy: future prospects". Int J Psychiatry Clin Pract 4 (4): 281–6. doi:10.1080/13651500050517830.
  22. ↑ Basile AS, Huang JM, Xie C, Webster D, Berlin C, Skolnick P (December 1996). "N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss". Nat. Med. 2 (12): 1338–43. doi:10.1038/nm1296-1338. PMID 8946832.
  23. ↑ Ernfors P, Canlon B (December 1996). "Aminoglycoside excitement silences hearing". Nat. Med. 2 (12): 1313–4. doi:10.1038/nm1296-1313. PMID 8946827. (Editorial)
  24. ↑ Post RM, Silberstein SD (October 1994). "Shared mechanisms in affective illness, epilepsy, and migraine". Neurology 44 (10 Suppl 7): S37–47. PMID 7969945.
  25. ↑ Tsiang H, Ceccaldi PE, Ermine A, Lockhart B, Guillemer S (March 1991). "Inhibition of rabies virus infection in cultured rat cortical neurons by an N-methyl-D-aspartate noncompetitive antagonist, MK-801". Antimicrob. Agents Chemother. 35 (3): 572–4. doi:10.1128/AAC.35.3.572. PMC 245052. PMID 1674849.
  26. ↑ Klockgether T, Turski L (October 1990). "NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats". Ann. Neurol. 28 (4): 539–46. doi:10.1002/ana.410280411. PMID 2252365.
  27. ↑ Faden AI, Lemke M, Simon RP, Noble LJ (1988). "N-methyl-D-aspartate antagonist MK801 improves outcome following traumatic spinal cord injury in rats: behavioral, anatomic, and neurochemical studies". J. Neurotrauma 5 (1): 33–45. doi:10.1089/neu.1988.5.33. PMID 3057216.
  28. 1 2 Olney JW, Labruyere J, Price MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263.
  29. ↑ Ellison G (February 1995). "The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias". Brain Res. Brain Res. Rev. 20 (2): 250–67. doi:10.1016/0165-0173(94)00014-G. PMID 7795658.
  30. ↑ 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". Ann. Neurol. 30 (6): 801–9. doi:10.1002/ana.410300609. PMID 1838680.
  31. ↑ 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". Neurochem. Res. 18 (12): 1263–9. doi:10.1007/BF00975046. PMID 7903796.
  32. ↑ 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 Neuropathol. 88 (6): 511–9. doi:10.1007/BF00296487. PMID 7879597.
  33. ↑ Fix AS, Horn JW, Wightman KA; 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". Exp. Neurol. 123 (2): 204–15. doi:10.1006/exnr.1993.1153. PMID 8405286.
  34. ↑ Carlezon WA, Wise RA (May 1996). "Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex". J. Neurosci. 16 (9): 3112–22. PMID 8622141.
  35. ↑ Herberg LJ, Rose IC (1989). "The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward". Psychopharmacology (Berl.) 99 (1): 87–90. doi:10.1007/BF00634458. PMID 2550989.
  36. ↑ Beardsley PM, Hayes BA, Balster RL (March 1990). "The self-administration of MK-801 can depend upon drug-reinforcement history, and its discriminative stimulus properties are phencyclidine-like in rhesus monkeys". J. Pharmacol. Exp. Ther. 252 (3): 953–9. PMID 2181113.
  37. ↑ Layer RT, Kaddis FG, Wallace LJ (January 1993). "The NMDA receptor antagonist M-801 elicits conditioned place preference in rats". Pharmacology, Biochemistry and Behaviour 44 (1): 245–7. doi:10.1016/0091-3057(93)90306-E.
  38. ↑ 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". Eur. J. Pharmacol. 317 (2–3): 191–6. doi:10.1016/S0014-2999(96)00747-9. PMID 8997600.
  39. ↑ Mozayani, A; Schrode, P; Carter, J; Danielson, TJ (Apr 23, 2003). "A multiple drug fatality involving MK-801 (dizocilpine), a mimic of phencyclidine.". Forensic Science International 133 (1-2): 113–7. doi:10.1016/S0379-0738(03)00070-7. PMID 12742697.
  40. ↑ Chang, M. Y.; Huang, Y. P.; Lee, T. W.; Chen, Y. L. (2012). "Synthesis of dizocilpine". Tetrahedron 68 (16): 3283–3287. doi:10.1016/j.tet.2012.03.007.

Further reading

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