Dizocilpine: Difference between revisions

'''Dizocilpine''' ([[International Nonproprietary Name|INN]]), also known as '''MK-801''', is a pore blocker of the ''N''-Methyl-<small>D</small>-aspartate ([[https://en.wikipedia.org/wiki/N-Methyl-D-aspartic_acid|NMDA]]) receptor, a [[glutamate receptor]], discovered by a team at Merck in 1982.<ref>{{ cite patent | country = US | status = Patent | number = 4399141 | title = 5-Alkyl or hydroxyalkyl substituted-10,11-imines & Anticonvulsant Use Thereof | gdate = 1983-08-16 | inventor = Anderson P, Christy ME, Evans BE | assign1 = Merck & Company Inc }}</ref> 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.<ref>{{cite journal | vauthors = Foster AC, Fagg GE | title = Neurobiology. Taking apart NMDA receptors | journal = Nature | volume = 329 | issue = 6138 | pages = 395–396 | year = 1987 | pmid = 2443852 | doi = 10.1038/329395a0 | s2cid = 5486568 }}</ref> Dizocilpine binds inside the [[ion channel]] of the [[receptor (biochemistry)|receptor]] at several of [[phencyclidine|PCP]]'s binding sites thus preventing the flow of [[ion]]s, including [[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.<ref>{{cite journal | vauthors = Huettner JE, Bean BP | title = Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 4 | pages = 1307–1311 | date = February 1988 | pmid = 2448800 | pmc = 279756 | doi = 10.1073/pnas.85.4.1307 | doi-access = free }}</ref> The drug acts as a potent [[anti-convulsant]] and probably has dissociative anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called [[Olney's lesions]] (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of [[long term potentiation]]<ref>{{cite journal | vauthors = Coan EJ, Saywood W, Collingridge GL | title = MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices | journal = Neuroscience Letters | volume = 80 | issue = 1 | pages = 111–114 | date = September 1987 | pmid = 2821457 | doi = 10.1016/0304-3940(87)90505-2 | s2cid = 268615 }}</ref> and has been found to impair the acquisition of difficult, but not easy, learning tasks  in rats<ref>{{cite journal | vauthors = Murray TK, Ridley RM, Snape MF, Cross AJ | title = The effect of dizocilpine (MK-801) on spatial and visual discrimination tasks in the rat | journal = Behavioural Pharmacology | volume = 6 | issue = 5 And 6 | pages = 540–549 | date = August 1995 | pmid = 11224361 | doi = 10.1097/00008877-199508000-00014 | s2cid = 29029744 }}</ref><ref>{{cite journal | vauthors = Murray TK, Ridley RM | title = The effect of dizocilpine (MK-801) on conditional discrimination learning in the rat | journal = Behavioural Pharmacology | volume = 8 | issue = 5 | pages = 383–388 | date = October 1997 | pmid = 9832977 | doi = 10.1097/00008877-199710000-00002 | s2cid = 27485569 }}</ref> and primates.<ref>{{cite journal | vauthors = Harder JA, Aboobaker AA, Hodgetts TC, Ridley RM | title = Learning impairments induced by glutamate blockade using dizocilpine (MK-801) in monkeys | journal = British Journal of Pharmacology | volume = 125 | issue = 5 | pages = 1013–1018 | date = November 1998 | pmid = 9846639 | pmc = 1565679 | doi = 10.1038/sj.bjp.0702178 }}</ref> Because of these effects of dizocilpine, the NMDA receptor pore blocker [[ketamine]] is used instead 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 uncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.