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MPP+

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(Redirected fromCyperquat)
Not to be confused withMPTPorMPPP.
MPP+
Skeletal formula of MPP+
Ball-and-stick model of the MPP+ cation
Names
Preferred IUPAC name
1-Methyl-4-phenylpyridin-1-ium
Other names
Cyperquat; 1-Methyl-4-phenylpyridinium;N-Methyl-4-phenylpyridine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 248-939-7
MeSH 1-Methyl-4-phenylpyridinium
UNII
  • InChI=1S/C12H12N/c1-13-9-7-12(8-10-13)11-5-3-2-4-6-11/h2-10H,1H3/q+1checkY
    Key: FMGYKKMPNATWHP-UHFFFAOYSA-NcheckY
  • C[n+]1ccc(cc1)c2ccccc2
Properties
C12H12N+
Molar mass 170.25 g/mol
Appearance White to beige powder
10 mg/mL
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).

MPP+(1-methyl-4-phenylpyridinium) is a positively charged organic molecule with thechemical formulaC12H12N+.It is aneurotoxinthat acts by interfering withoxidative phosphorylationinmitochondriaby inhibitingcomplex I,leading to the depletion ofATPand eventualcell death.[1]

MPP+arises in the body as the toxic metabolite of the closely related compoundMPTP.MPTP is converted in thebraininto MPP+by theenzymeMAO-B,ultimately causingparkinsonisminprimatesby killing certaindopamine-producingneuronsin thesubstantia nigra.The ability for MPP+to induceParkinson's diseasehas made it an important compound in Parkinson's research since this property was discovered in 1983.[2][3]

Thechloridesaltof MPP+found use in the 1970s as anherbicideunder the trade namecyperquat.[3]Though no longer in use as an herbicide, cyperquat's closely related structural analogparaquatstill finds widespread usage, raising some safety concerns.

History[edit]

MPP+has been known since at least the 1920s, with a synthesis of the compound being published in a German chemistry journal in 1923.[4]Its neurotoxic effects, however, were not known until much later, with the first paper definitively identifying MPP+as a Parkinson's-inducing poison being published in 1983.[5]This paper followed a string of poisonings that took place in San Jose, California in 1982 in which users of an illicitly synthesized analog ofmeperidinewere presenting to hospital emergency rooms with symptoms of Parkinson's.[2]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.[2]The researchers discovered that the opiates were tainted withMPTP,which is the biological precursor to the neurotoxic MPP+.[2]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.[6]The student came down with symptoms of Parkinson's disease, and his synthesized product was found to be heavily contaminated with MPTP.[6]

The discovery that MPP+could reliably and irreversibly induce Parkinson's disease in mammals reignited interest in Parkinson's research, which had previously been dormant for decades.[7]Following the revelation, MPP+and MPTP sold out in virtually all chemical catalogs, reappearing months later with a 100-fold price increase.[7]

Synthesis[edit]

Laboratory[edit]

Reaction scheme for the laboratory synthesis of MPP+.

MPP+can be readily synthesized in the laboratory, with Zhang and colleagues publishing a representative synthesis in 2017.[8]The synthesis involves reacting 4-phenylpyridine withmethyl iodidein acetonitrile solvent at reflux for 24 hours.[8]An inert atmosphere is used to ensure a quantitative yield.[8]The product is formed as the iodide salt, and the reaction proceeds via anSN2pathway.[8]The industrial synthesis of MPP+for sale as the herbicide cyperquat usedmethyl chlorideas the source of the methyl group.

Biological[edit]

MPP+is producedin vivofrom the precursor MPTP. The process involves two successive oxidations of the molecule bymonoamine oxidase Bto form the final MPP+product.[9]This metabolic process occurs predominantly inastrocytesin the brain.[9]

Metabolism of MPTP to MPP+in cerebral astrocytes.

Mechanism of toxicity[edit]

MPP+exhibits its toxicity mainly by promoting the formation of reactivefree radicalsin the mitochondria of dopaminergic neurons in thesubstantia nigra.[9][10]MPP+can siphon electrons from the mitochondrialelectron transport chainat complex I and be reduced, in the process forming radicalreactive oxygen specieswhich go on to cause further, generalized cellular damage.[9][10]In addition, the overall inhibition of the electron transport chain eventually leads to stuntedATPproduction and eventual death of the dopaminergic neurons, which ultimately displays itself clinically as symptoms of Parkinson's disease.[1][9][10]

MPP+also displays toxicity by inhibiting the synthesis ofcatecholamines,reducing levels ofdopamineandcardiacnorepinephrine,and inactivatingtyrosine hydroxylase.[1]

The mechanism of uptake of MPP+is important to its toxicity. MPP+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 theblood-brain barrier.[9]Furthermore, MPP+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+cannot readily diffuse across thelipid bilayerthat composes cellular membranes.[9]

Unlike MPP+,its common biological precursor MPTP is a lipid-soluble molecule that diffuses readily across the blood-brain barrier.[9]MPTP itself is not cytotoxic, however, and must be metabolized to MPP+by MAO-B to show any signs of toxicity.[9]The oxidation of MPTP to MPP+is a process that can be catalyzed only by MAO-B, and cells that express other forms of MAO do not show any MPP+production.[9]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+toxicity.[11]

Studies in rats and mice show that various compounds, includingnobiletin,aflavonoidfound in citrus, can rescue dopaminergic neurons from degeneration caused by treatment with MPP+.[10]The specific mechanism of protection, however, remains unknown.[10]

Uses[edit]

In scientific research[edit]

MPP+and its precursor MPTP are widely used inanimal models of Parkinson's diseaseto irreversibly induce the disease.[2]Excellent selectivity and dose control can be achieved by injecting the compound directly into cell types of interest.[9][10]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+.[7][10]Commonly studied compounds include variousMAO inhibitorsand generalantioxidants.[7][10]While some of these compounds are quite effective at stopping theneurotoxiceffects of MPP+,further research is needed to establish their potential efficacy in treating clinical Parkinson's.[10]

The revelation that MPP+causes the death of dopaminergic neurons and ultimately induces symptoms of Parkinson's disease was crucial in establishing the lack ofdopamineas central to Parkinson's disease.[2]Levodopaor L-DOPA came into common use as an anti-Parkinson's medication thanks to the results brought about by research using MPP+.[2]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+still being widely used in early trials to test efficacy.[12]

As apesticide[edit]

Paraquat, an herbicide structurally similar to cyperquat, is still widely used in agriculture.[3]The molecule is depicted here as the chloride salt.

MPP+,sold as the chloride salt under the brand name cyperquat, was used briefly in the 1970s as anherbicideto protect crops against nutsedge, a member of thecyperusgenus of plants.[3]MPP+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.[9]While cyperquat is no longer used as an herbicide, a closely related compound namedparaquatis.[3]Given the structural similarities, some[3]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+,since paraquat does not bind to complex I in the mitochondrial electron transport chain, and thus its toxic effects cannot be realized.[11]

Safety[edit]

MPP+is commonly sold as the water-soluble iodide salt and is a white-to-beige powder.[13]Specific toxicological data on the compound is somewhat lacking, but one MSDS quotes anLD50of 29 mg/kg via anintraperitonealroute and 22.3 mg/kg via a subcutaneous route of exposure.[14]Both values come from a mouse model system.[14]

MPP+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+to cross the blood-brain barrier and freely diffuse acrosscellular membranes.[11]

There is no specific antidote to MPP+poisoning. Clinicians are advised to treat exposure symptomatically.[14]

References[edit]

  1. ^abcPubChem Compound entry on MPP+
  2. ^abcdefgLocklear M (18 May 2016)."How tainted drugs" froze "young people—but kickstarted Parkinson's research".Ars Technica.
  3. ^abcdefWolf LK (November 25, 2013)."The Pesticide Connection".Chemical & Engineering News.91(47): 11–15.doi:10.1021/cen-09147-cover.
  4. ^Emmert B (1923). "Über chinhydronartige Verbindungen der N,N′‐Dialkyl‐[dihydro‐γ,γ′‐dipyridyle]".Chemische Berichte.56:500.
  5. ^Langston JW, Ballard P, Tetrud JW, Irwin I (February 1983). "Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis".Science.219(4587): 979–80.doi:10.1126/science.6823561.PMID6823561.
  6. ^abFahn S (1996-12-26). "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".New England Journal of Medicine.335(26): 2002–2003.doi:10.1056/NEJM199612263352618.ISSN0028-4793.
  7. ^abcdLangston JW (2017-03-06)."The MPTP Story".Journal of Parkinson's Disease.7(s1): S11–S22.doi:10.3233/jpd-179006.PMC5345642.PMID28282815.
  8. ^abcdZhang Y, Zhou TY, Zhang KD, Dai JL, Zhu YY, Zhao X (June 2014). "Encapsulation enhanced dimerization of a series of 4-aryl-N-methylpyridinium derivatives in water: new building blocks for self-assembly in aqueous media".Chemistry: An Asian Journal.9(6): 1530–4.doi:10.1002/asia.201400006.PMID24756985.
  9. ^abcdefghijklKopin IJ (November 1987)."MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson's disease".Environmental Health Perspectives.75:45–51.doi:10.1289/ehp.877545.PMC1474453.PMID3319563.
  10. ^abcdefghiJeong KH, Jeon MT, Kim HD, Jung UJ, Jang MC, Chu JW, Yang SJ, Choi IY, Choi MS, Kim SR (April 2015). "Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease".Journal of Medicinal Food.18(4): 409–14.doi:10.1089/jmf.2014.3241.PMID25325362.
  11. ^abcHassan MN, Thakar JN, Grimes JD (1987). "Cyperquat (MPP+), but not MPTP or Paraquat Inhibits Oxygen Consumption in Mitochondria from Rat Striatum ".The Basal Ganglia II.Advances in Behavioral Biology. Vol. 32. Boston, MA: Springer. pp. 169–173.doi:10.1007/978-1-4684-5347-8_11.ISBN9781468453492.
  12. ^"Therapies in Development for Parkinson's Disease".The Michael J. Fox Foundation for Parkinson's Research | Parkinson's Disease.Retrieved2018-04-26.
  13. ^"MPP+iodide D048 ".Sigma-Aldrich.Retrieved2018-05-02.
  14. ^abc"MPP+ Iodide Safety Data Sheet"(PDF).2017-03-10.
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