| Revision as of 12:40, 23 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{chembox}} taken from revid 460250116 of page MPP+ for the Chem/Drugbox validation project (updated: 'CASNo'). |
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{{DISPLAYTITLE:MPP<sup>+</sup>}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Distinguish|MPTP|MPPP}} |
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{{chembox |
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{{chembox |
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|ImageFile=MPP+.svg |
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| Name = MPP<sup>+</sup> |
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| ImageFile = MPP+.svg |
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|ImageSize=200px |
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| ImageFile1 = MPP+ cation ball.png |
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|IUPACName=1-Methyl-4-phenylpyridin-1-ium |
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| ImageSize = 200px |
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|OtherNames=Cyperquat |
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| ImageAlt = Skeletal formula of MPP<sup>+</sup> |
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|Section1= {{Chembox Identifiers |
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| ImageSize1 = 210 |
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| CASNo = <!-- blanked - oldvalue: 39794-99-5 --> |
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| ImageAlt1 = Ball-and-stick model of the MPP<sup>+</sup> cation |
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| PubChem=39484 |
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| PIN = 1-Methyl-4-phenylpyridin-1-ium |
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| EINECS=248-939-7 |
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| OtherNames = Cyperquat; 1-Methyl-4-phenylpyridinium; ''N''-Methyl-4-phenylpyridine |
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| Section1 = {{Chembox Identifiers |
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| IUPHAR_ligand = 4568 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo=39794-99-5 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = MRP3DNB9K9 |
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| PubChem=39484 |
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| EINECS=248-939-7 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 311617 |
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| ChEMBL = 311617 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 36101 |
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| ChemSpiderID = 36101 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 641 |
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| ChEBI = 641 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C12H12N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-10H,1H3/q+1 |
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| StdInChI = 1S/C12H12N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-10H,1H3/q+1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = FMGYKKMPNATWHP-UHFFFAOYSA-N |
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| StdInChIKey = FMGYKKMPNATWHP-UHFFFAOYSA-N |
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| SMILES=C1=cc=c(c=c1)c2=cc=cc=c2 |
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| SMILES=C1ccc(cc1)c2ccccc2 |
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| MeSHName = 1-Methyl-4-phenylpyridinium |
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| MeSHName = 1-Methyl-4-phenylpyridinium |
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}} |
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}} |
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|Section2= {{Chembox Properties |
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| Section2 = {{Chembox Properties |
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| Formula=C<sub>12</sub>H<sub>12</sub>N<sup>+</sup> |
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| Formula=C<sub>12</sub>H<sub>12</sub>N<sup>+</sup> |
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| MolarMass=170.25 g/mol |
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| MolarMass=170.25 g/mol |
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| Appearance= |
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| Appearance=White to beige powder |
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| Density= |
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| Density= |
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| MeltingPt= |
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| BoilingPt= |
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| BoilingPt= |
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| Solubility= |
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| Solubility=10 mg/mL |
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}} |
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}} |
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|Section3= {{Chembox Hazards |
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| Section3 = {{Chembox Hazards |
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| MainHazards= |
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| MainHazards= |
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| FlashPt= |
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| FlashPt= |
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| AutoignitionPt = |
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| Autoignition= |
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}} |
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}} |
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| Section4 = |
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| Section5 = |
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| Section6 = |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 462095633 |
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}} |
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}} |
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'''MPP<sup>+</sup>''' ('''1-methyl-4-phenylpyridinium''') is a positively charged organic molecule with the ] C<sub>12</sub>H<sub>12</sub>N<sup>+</sup>. It is a ] that acts by interfering with ] in ] by inhibiting ], leading to the depletion of ] and eventual ].<ref name="pubchem"></ref> |
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MPP<sup>+</sup> arises in the body as the toxic metabolite of the closely related compound ]. MPTP is converted in the ] into MPP<sup>+</sup> by the ] ], ultimately causing ] in ]s by killing certain ]-producing ] in the ]. The ability for MPP<sup>+</sup> to induce ] has made it an important compound in Parkinson's research since this property was discovered in 1983.<ref name="Locklear_2016">{{cite news | first = Mallory | last = Locklear | name-list-style = vanc | date = 18 May 2016 | url = https://arstechnica.com/science/2016/05/medical-mystery-how-tainted-drugs-froze-young-people-but-kickstarted-parkinsons-research/ | title=How tainted drugs "froze" young people—but kickstarted Parkinson's research | work = Ars Technica }}</ref><ref name="Wolf_2013">{{Cite journal | url = https://cen.acs.org/articles/91/i47/Pesticide-Connection.html | title = The Pesticide Connection | date = November 25, 2013 | volume = 91 | issue = 47 | pages = 11–15 | journal = Chemical & Engineering News|last=Wolf|first=Lauren K. | name-list-style = vanc | doi = 10.1021/cen-09147-cover }}</ref> |
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The ] ] of MPP<sup>+</sup> found use in the 1970s as an ] under the trade name '''cyperquat'''.<ref name="Wolf_2013" /> Though no longer in use as an herbicide, cyperquat's closely related structural analog ] still finds widespread usage, raising some safety concerns. |
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== History == |
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MPP<sup>+</sup> has been known since at least the 1920s, with a synthesis of the compound being published in a German chemistry journal in 1923.<ref>{{Cite journal|last=Emmert|first=Bruno | name-list-style = vanc |date=1923|title=Über chinhydronartige Verbindungen der N,N′-Dialkyl-|journal=Chemische Berichte|volume=56|pages=500}}</ref> Its neurotoxic effects, however, were not known until much later, with the first paper definitively identifying MPP<sup>+</sup> as a Parkinson's-inducing poison being published in 1983.<ref>{{cite journal | vauthors = Langston JW, Ballard P, Tetrud JW, Irwin I | title = Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis | journal = Science | volume = 219 | issue = 4587 | pages = 979–80 | date = February 1983 | pmid = 6823561 | doi=10.1126/science.6823561| bibcode = 1983Sci...219..979L }}</ref> This paper followed a string of poisonings that took place in San Jose, California in 1982 in which users of an illicitly synthesized analog of ] were presenting to hospital emergency rooms with symptoms of Parkinson's.<ref name="Locklear_2016" /> Since most of the patients were young and otherwise healthy and Parkinson's disease tends to afflict people at a much older age, researchers at the hospital began to scrutinize the illicitly synthesized opiates that the patients had ingested.<ref name="Locklear_2016" /> The researchers discovered that the opiates were tainted with ], which is the biological precursor to the neurotoxic MPP<sup>+</sup>.<ref name="Locklear_2016" /> The MPTP was present in the illicitly synthesized meperidine analog as an impurity, which had a precedent in a 1976 case involving a chemistry graduate student synthesizing meperidine and injecting the resulting product into himself.<ref name="Fahn_1996">{{cite journal | last = Fahn | first = Stanley | name-list-style = vanc |date=1996-12-26|title=The Case of the Frozen Addicts: How the solution of an extraordinary medical mystery spawned a revolution in the understanding and treatment of Parkinson's disease |journal=New England Journal of Medicine|volume=335|issue=26|pages=2002–2003|doi=10.1056/NEJM199612263352618|issn=0028-4793 }}</ref> The student came down with symptoms of Parkinson's disease, and his synthesized product was found to be heavily contaminated with MPTP.<ref name="Fahn_1996" /> |
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The discovery that MPP<sup>+</sup> could reliably and irreversibly induce Parkinson's disease in mammals reignited interest in Parkinson's research, which had previously been dormant for decades.<ref name="Langston_2017">{{cite journal | vauthors = Langston JW | title = The MPTP Story | journal = Journal of Parkinson's Disease | volume = 7 | issue = s1 | pages = S11–S22 | date = 2017-03-06 | pmid = 28282815 | pmc = 5345642 | doi = 10.3233/jpd-179006 }}</ref> Following the revelation, MPP<sup>+</sup> and MPTP sold out in virtually all chemical catalogs, reappearing months later with a 100-fold price increase.<ref name="Langston_2017" /> |
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== Synthesis == |
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=== Laboratory === |
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MPP<sup>+</sup> can be readily synthesized in the laboratory, with Zhang and colleagues publishing a representative synthesis in 2017.<ref name="Zhang_2014">{{cite journal | vauthors = Zhang Y, Zhou TY, Zhang KD, Dai JL, Zhu YY, Zhao X | title = Encapsulation enhanced dimerization of a series of 4-aryl-N-methylpyridinium derivatives in water: new building blocks for self-assembly in aqueous media | journal = Chemistry: An Asian Journal | volume = 9 | issue = 6 | pages = 1530–4 | date = June 2014 | pmid = 24756985 | doi = 10.1002/asia.201400006 }}</ref> The synthesis involves reacting 4-phenylpyridine with ] in acetonitrile solvent at reflux for 24 hours.<ref name="Zhang_2014" /> An inert atmosphere is used to ensure a quantitative yield.<ref name="Zhang_2014" /> The product is formed as the iodide salt, and the reaction proceeds via an ] pathway.<ref name="Zhang_2014" /> The industrial synthesis of MPP<sup>+</sup> for sale as the herbicide cyperquat used ] as the source of the methyl group. |
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=== Biological === |
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MPP<sup>+</sup> is produced ''in vivo'' from the precursor MPTP. The process involves two successive oxidations of the molecule by ] to form the final MPP<sup>+</sup> product.<ref name="Kopin_1987">{{cite journal | vauthors = Kopin IJ | title = MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson's disease | journal = Environmental Health Perspectives | volume = 75 | pages = 45–51 | date = November 1987 | pmid = 3319563 | pmc = 1474453 | doi = 10.1289/ehp.877545 }}</ref> This metabolic process occurs predominantly in ]s in the brain.<ref name="Kopin_1987" /> |
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] |
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== Mechanism of toxicity == |
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MPP<sup>+</sup> exhibits its toxicity mainly by promoting the formation of reactive ] in the mitochondria of dopaminergic neurons in the ].<ref name="Kopin_1987" /><ref name="Jeong_2015">{{cite journal | vauthors = Jeong KH, Jeon MT, Kim HD, Jung UJ, Jang MC, Chu JW, Yang SJ, Choi IY, Choi MS, Kim SR | title = Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease | journal = Journal of Medicinal Food | volume = 18 | issue = 4 | pages = 409–14 | date = April 2015 | pmid = 25325362 | doi = 10.1089/jmf.2014.3241 }}</ref> MPP<sup>+</sup> can siphon electrons from the mitochondrial ] at complex I and be reduced, in the process forming radical ] which go on to cause further, generalized cellular damage.<ref name="Kopin_1987" /><ref name="Jeong_2015" /> In addition, the overall inhibition of the electron transport chain eventually leads to stunted ] production and eventual death of the dopaminergic neurons, which ultimately displays itself clinically as symptoms of Parkinson's disease.<ref name="pubchem" /><ref name="Kopin_1987" /><ref name="Jeong_2015" /> |
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MPP<sup>+</sup> also displays toxicity by inhibiting the synthesis of ]s, reducing levels of ] and ] ], and inactivating ].<ref name="pubchem" /> |
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The mechanism of uptake of MPP<sup>+</sup> is important to its toxicity. MPP<sup>+</sup> injected as an aqueous solution into the bloodstream causes no symptoms of Parkinsonism in test subjects, since the highly charged molecule is unable to diffuse through the ].<ref name="Kopin_1987" /> Furthermore, MPP<sup>+</sup> shows little toxicity to cells other than dopaminergic neurons, suggesting that these neurons have a unique process by which they can uptake the molecule, since, being charged, MPP<sup>+</sup> cannot readily diffuse across the ] that composes cellular membranes.<ref name="Kopin_1987" /> |
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Unlike MPP<sup>+</sup>, its common biological precursor MPTP is a lipid-soluble molecule that diffuses readily across the blood-brain barrier.<ref name="Kopin_1987" /> MPTP itself is not cytotoxic, however, and must be metabolized to MPP<sup>+</sup> by MAO-B to show any signs of toxicity.<ref name="Kopin_1987" /> The oxidation of MPTP to MPP<sup>+</sup> is a process that can be catalyzed only by MAO-B, and cells that express other forms of MAO do not show any MPP<sup>+</sup> production.<ref name="Kopin_1987" /> Studies in which MAO-B was selectively inhibited showed that MPTP had no toxic effect, further cementing the crucial role of MAO-B in MPTP and MPP<sup>+</sup> toxicity.<ref name="Hassan_1987">{{cite book | title = The Basal Ganglia II |volume = 32| vauthors = Hassan MN, Thakar JN, Grimes JD | date = 1987 | publisher = Springer | location = Boston, MA | isbn = 9781468453492 | series = Advances in Behavioral Biology | pages = 169–173 | doi = 10.1007/978-1-4684-5347-8_11 |chapter = Cyperquat (MPP<sup>+</sup>), but not MPTP or Paraquat Inhibits Oxygen Consumption in Mitochondria from Rat Striatum}}</ref> |
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Studies in rats and mice show that various compounds, including ], a ] found in citrus, can rescue dopaminergic neurons from degeneration caused by treatment with MPP<sup>+</sup>.<ref name="Jeong_2015" /> The specific mechanism of protection, however, remains unknown.<ref name="Jeong_2015" /> |
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== Uses == |
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=== In scientific research === |
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MPP<sup>+</sup> and its precursor MPTP are widely used in ] to irreversibly induce the disease.<ref name="Locklear_2016" /> Excellent selectivity and dose control can be achieved by injecting the compound directly into cell types of interest.<ref name="Kopin_1987" /><ref name="Jeong_2015" /> Most modern studies use rats as a model system, and much research is directed at identifying compounds that can attenuate or reverse the effects of MPP<sup>+</sup>.<ref name="Langston_2017" /><ref name="Jeong_2015" /> Commonly studied compounds include various ] and general ]s.<ref name="Langston_2017" /><ref name="Jeong_2015" /> While some of these compounds are quite effective at stopping the ] effects of MPP<sup>+</sup>, further research is needed to establish their potential efficacy in treating clinical Parkinson's.<ref name="Jeong_2015" /> |
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The revelation that MPP<sup>+</sup> causes the death of dopaminergic neurons and ultimately induces symptoms of Parkinson's disease was crucial in establishing the lack of ] as central to Parkinson's disease.<ref name="Locklear_2016" /> ] or L-DOPA came into common use as an anti-Parkinson's medication thanks to the results brought about by research using MPP<sup>+</sup>.<ref name="Locklear_2016" /> Further medications are in trial to treat the progression of the disease itself as well as the motor and non-motor symptoms associated with Parkinson's, with MPP<sup>+</sup> still being widely used in early trials to test efficacy.<ref>{{Cite web|url=https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?therapies-in-development&navid=therapies-in-development|title=Therapies in Development for Parkinson's Disease|website=The Michael J. Fox Foundation for Parkinson's Research {{!}} Parkinson's Disease|access-date=2018-04-26}}</ref> |
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=== As a ] === |
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MPP<sup>+</sup>, sold as the chloride salt under the brand name cyperquat, was used briefly in the 1970s as an ] to protect crops against nutsedge, a member of the ] genus of plants.<ref name="Wolf_2013" /> MPP<sup>+</sup> as a salt has much lower acute toxicity than its precursor MPTP due to the inability of the former to pass through the blood-brain barrier and ultimately access the only cells that will permit its uptake, the dopaminergic neurons.<ref name="Kopin_1987" /> While cyperquat is no longer used as an herbicide, a closely related compound named ] is.<ref name="Wolf_2013" /> Given the structural similarities, some<ref name="Wolf_2013" /> have raised concerns about paraquat's active use as an herbicide for those handling it. However, studies have shown paraquat to be far less neurotoxic than MPP<sup>+</sup>, since paraquat does not bind to complex I in the mitochondrial electron transport chain, and thus its toxic effects cannot be realized.<ref name="Hassan_1987" /> |
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== Safety == |
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MPP<sup>+</sup> is commonly sold as the water-soluble iodide salt and is a white-to-beige powder.<ref>{{Cite web|url=https://www.sigmaaldrich.com/catalog/product/sigma/d048?lang=en®ion=US|title=MPP<SUP>+</SUP> iodide D048|website=Sigma-Aldrich|access-date=2018-05-02}}</ref> Specific toxicological data on the compound is somewhat lacking, but one MSDS quotes an ] of 29 mg/kg via an ] route and 22.3 mg/kg via a subcutaneous route of exposure.<ref name="MSDS_MPP">{{Cite web|url=https://www.caymanchem.com/msdss/16958m.pdf|title=MPP+ Iodide Safety Data Sheet |date=2017-03-10 }}</ref> Both values come from a mouse model system.<ref name="MSDS_MPP" /> |
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MPP<sup>+</sup> encountered in the salt form is far less toxic by ingestion, inhalation, and skin exposure than its biological precursor MPTP, due to the inability of MPP<sup>+</sup> to cross the blood-brain barrier and freely diffuse across ].<ref name="Hassan_1987" /> |
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There is no specific antidote to MPP<sup>+</sup> poisoning. Clinicians are advised to treat exposure symptomatically.<ref name="MSDS_MPP" /> |
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== References == |
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{{Reflist}} |
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{{Herbicides}} |
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{{Monoamine neurotoxins}} |
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__FORCETOC__ |
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