Desmethylprodine

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Not to be confused with MαPPP (stimulant designer drug), MPTP (neurotoxic impurity of desmethylprodine synthesis) or MPP+ (neurotoxic metabolite of MPTP).

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Desmethylprodine
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Clinical data
Other names4-propionyloxy-4-phenyl-N-methylpiperidine, MPPP, 3-desmethylprodine
Legal status
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Identifiers
  • (1-Methyl-4-phenylpiperidin-4-yl) propanoate
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Chemical and physical data
FormulaC15H21NO2
Molar mass247.338 g·mol−1
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Desmethylprodine or 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP, Ro 2-0718) is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche.[1] Desmethylprodine has been labeled by the DEA as a Schedule I drug in the United States. It is an analog of pethidine (meperidine) a Schedule II drug. Chemically, it is a reversed ester of pethidine which has about 70% of the potency of morphine. Unlike its derivative prodine, 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

Desmethylprodine was first synthesized in 1947 at Hoffman-LaRoche Laboratories by Albert Ziering and John Lee. They found that it produced effects similar to morphine when 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 analgesic alphaprodine (Nisentil, Prisilidine), a very closely related compound.[2]

In the United States, MPPP is now in Schedule I of the Controlled Substances Act with a zero aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride.[5] It is listed under the Single Convention on Narcotic Drugs and is controlled in most countries in the same fashion as is morphine.

Toxic impurity

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, because 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 of Parkinson's disease and was hospitalized. Physicians were perplexed, because Parkinson's disease would be a great rarity in someone so young, but L-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 called 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that specifically targets dopamine-producing neurons.[4][6] The intermediate tertiary alcohol is liable to dehydration in acidic conditions if the reaction temperature rises above 30 °C. Kidston did not realize this and esterified the intermediate with propionic anhydride at an elevated temperature. Consequently, he produced MPTP 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 enzyme MAO-B, which is expressed in glial cells. This selectively kills brain tissue in the area of the brain called the substantia nigra and causes permanent Parkinsonian symptoms.[10]

Analogs

Structural analogs of desmethylprodine with different N-substituents than a methyl group on the piperidine have been investigated. Several of these have significantly greater in vitro potency compared to desmethylprodine.[11][12][13]

See also

References

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  1. ^ Page Template:Citation/styles.css has no content.US 2765314, Schmidle CJ, Mansfield RC, "Preparation of Esters", issued Script error: No such module "auto date formatter"., assigned to Rohm and Haas 
  2. ^ a b c Page Module:Citation/CS1/styles.css has no content.Reynolds AK, Randall LO (1957). Morphine & Allied Drugs. p. 310.
  3. ^ Page Module:Citation/CS1/styles.css has no content.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. PMID 18919744.
  4. ^ a b Page Module:Citation/CS1/styles.css has no content.Schwarcz J (2005). "Aim high: synthetic opiates deliver surprising side effects". Canadian Chemical News. 57 (10): 10.
  5. ^ Page Module:Citation/CS1/styles.css has no content."Quotas - 2014". DEA Diversion Control Division. Archived from the original on 2016-03-04. Retrieved 2016-02-26.
  6. ^ Page Module:Citation/CS1/styles.css has no content.Gibb BJ (2007). The Rough Guide to the Brain. London: Rough Guides Ltd. p. 166. ISBN 978-1-4093-5993-7.
  7. ^ Page Module:Citation/CS1/styles.css has no content.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. PMID 6148225.
  8. ^ Page Module:Citation/CS1/styles.css has no content.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. PMID 298352. S2CID 44304872.
  9. ^ Page Module:Citation/CS1/styles.css has no content.Wallis C (1985-04-08). "Surprising Clue to Parkinson's". Time. Archived from the original on February 11, 2007. Retrieved 2024-11-22.
  10. ^ Page Module:Citation/CS1/styles.css has no content.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. PMID 11768626. S2CID 2834254.
  11. ^ Page Module:Citation/CS1/styles.css has no content.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. Bibcode:1958JAChS..80.4916E. doi:10.1021/ja01551a038.
  12. ^ Page Module:Citation/CS1/styles.css has no content.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. PMID 14056434.
  13. ^ Page Module:Citation/CS1/styles.css has no content.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. PMID 14406754.

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