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Desmethylprodine

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(Redirected fromMPPP)
"MPPP" redirects here. For other uses, seeMPPP (disambiguation).
Not to be confused withMαPPP(stimulant designer drug),MPTP(neurotoxic impurity of desmethylprodine synthesis) orMPP+(neurotoxic metabolite of MPTP).
Desmethylprodine
Skeletal formula
Ball-and-stick model of desmethylprodine
Clinical data
Other names4-propionyloxy-4-phenyl-N-methylpiperidine, MPPP, 3-desmethylprodine
Legal status
Legal status
Identifiers
  • (1-Methyl-4-phenylpiperidin-4-yl) propanoate
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC15H21NO2
Molar mass247.338g·mol−1
3D model (JSmol)
  • O=C(CC)OC1(CCN(CC1)C)C2=CC=CC=C2
  • InChI=1S/C15H21NO2/c1-3-14(17)18-15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3checkY
  • Key:BCQMRZRAWHNSBF-UHFFFAOYSA-NcheckY
(verify)

Desmethylprodineor1-methyl-4-phenyl-4-propionoxypiperidine(MPPP, Ro 2-0718) is anopioidanalgesicdrug developed in the 1940s by researchers atHoffmann-La Roche.[1]Desmethylprodinehas been labeled by theDEAas aSchedule Idrug in the United States. It is ananalogofpethidine(meperidine) aSchedule IIdrug. Chemically, it is a reversedesterof pethidine which has about 70% of the potency ofmorphine.Unlike its derivativeprodine,it does not exhibit optical isomerism.[2]It was reported to have 30 times the activity of pethidine and a greater analgesic effect than morphine in rats, and it was demonstrated to cause central nervous system stimulation in mice.[2]

History

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Desmethylprodine was first synthesized in 1947 at Hoffman-LaRoche Laboratories by Albert Ziering and John Lee. They found that it produced effects similar tomorphinewhen administered to rats.[3]Ziering had been searching for synthetic painkillers that were less addictive than morphine. The new drug was a slight variant of pethidine. It was found to be no more effective than pethidine and was never marketed.[4]This research produced the analgesicalphaprodine(Nisentil, Prisilidine), a very closely related compound.[2]

In 1976, a 23-year-old graduate student in chemistry named Barry Kidston was searching for a way to make a legal recreational drug. Having read the paper by Ziering and Lee, he deduced that he could make a drug with pethidine's effects without its legal restrictions, since desmethylprodine is a different molecule and had never been addressed by law. Kidston successfully synthesized and used desmethylprodine for several months, after which he suddenly came down with the symptoms ofParkinson's diseaseand was hospitalized. Physicians were perplexed, since Parkinson's disease would be a great rarity in someone so young, butL-dopa,the standard drug for Parkinson's, relieved his symptoms. L-dopa is a precursor for dopamine, the neurotransmitter whose lack produces Parkinson's symptoms. It was later found that his development of Parkinson's was due to a common impurity in the synthesis of MPPP calledMPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine),aneurotoxinthat specifically targets dopamine producing neurons.[4][5]

In the United States, MPPP is now in Schedule I of theControlled Substances Actwith a zero aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride.[6]It is listed under theSingle Convention on Narcotic Drugsand is controlled in most countries in the same fashion as is morphine.

Toxic impurity

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The intermediatetertiary alcoholis liable to dehydration in acidic conditions if the reaction temperature rises above 30 °C. Kidston did not realize this and esterified the intermediate withpropionic anhydrideat an elevated temperature. Consequently,MPTPwas formed as a major impurity.[7]

1-Methyl-4-phenylpyridinium(MPP+), a metabolite of MPTP, causes rapid onset of irreversible symptoms similar to Parkinson's disease.[8][9]MPTP is metabolized to the neurotoxin MPP+by the enzymeMAO-B,which is expressed in glial cells. This selectively kills brain tissue in the area of the brain called thesubstantia nigraand causes permanent Parkinsonian symptoms.[10]

Analogs

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Structural analogsof desmethylprodine with differentN-substituents than amethyl groupon thepiperidinehave been investigated. Several of these have significantly greaterin vitropotency compared to desmethylprodine.[11][12][13]

See also

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References

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  1. ^US 2765314,Schmidle CJ, Mansfield RC, "Preparation of Esters", issued 2 October 1956, assigned to Rohm and Haas
  2. ^abcReynolds AK, Randall LO (1957).Morphine & Allied Drugs.p. 310.
  3. ^Ziering A, Lee J (November 1947). "Piperidine derivatives; 1,3-dialkyl-4-aryl-4-acyloxypiperidines".The Journal of Organic Chemistry.12(6): 911–4.doi:10.1021/jo01170a024.PMID18919744.
  4. ^abSchwarcz J (2005)."Aim high: synthetic opiates deliver surprising side effects".Canadian Chemical News.57(10): 10.
  5. ^Gibb BJ (2007).The Rough Guide to the Brain.London: Rough Guides Ltd. p. 166.ISBN978-1-4093-5993-7.
  6. ^"Quotas - 2014".DEA Diversion Control Division.Archived fromthe originalon 2016-03-04.Retrieved2016-02-26.
  7. ^Johannessen JN, Markey SP (July 1984). "Assessment of the opiate properties of two constituents of a toxic illicit drug mixture".Drug and Alcohol Dependence.13(4): 367–74.doi:10.1016/0376-8716(84)90004-8.PMID6148225.
  8. ^Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (December 1979). "Chronic Parkinsonism secondary to intravenous injection of meperidine analogues".Psychiatry Research.1(3): 249–54.doi:10.1016/0165-1781(79)90006-4.PMID298352.S2CID44304872.
  9. ^Wallis C (2001-06-24)."Surprising Clue to Parkinson's".Time.Archived fromthe originalon February 11, 2007.Retrieved2010-05-13.
  10. ^Schmidt N, Ferger B (2001). "Neurochemical findings in the MPTP model of Parkinson's disease".Journal of Neural Transmission.108(11): 1263–82.doi:10.1007/s007020100004.PMID11768626.S2CID2834254.
  11. ^Elpern B, Wetterau W, Carabateas P, Grumbach L (1958). "Strong Analgesics. The Preparation of Some 4-Acyloxy-1-aralkyl-4-phenylpiperidines".Journal of the American Chemical Society.80(18): 4916–4918.doi:10.1021/ja01551a038.
  12. ^Carabateas PM, Grumbach L (September 1962). "Strong Analgesics. Some 1-Substituted 4-Phenyl-4-Propionoxypiperidines".Journal of Medicinal and Pharmaceutical Chemistry.91(5): 913–9.doi:10.1021/jm01240a003.PMID14056434.
  13. ^Janssen PA, Eddy NB (February 1960). "Compounds related to pethidine-IV. New general chemical methods of increasing the analgesic activity of pethidine".Journal of Medicinal and Pharmaceutical Chemistry.2:31–45.doi:10.1021/jm50008a003.PMID14406754.
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