Desmethylprodine

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"MPPP" redirects here. For other uses, see MPPP (disambiguation).
Not to be confused with MαPPP (stimulant designer drug), MPTP (neurotoxic impurity of desmethylprodine synthesis) or MPP+ (neurotoxic metabolite of MPTP).
Desmethylprodine
MPPP.svg
Systematic (IUPAC) name
(1-methyl-4-phenylpiperidin-4-yl) propanoate
Clinical data
Legal status Schedule I (US)
Identifiers
CAS number 13147-09-6
ATC code ?
PubChem CID 61583
DrugBank DB01478
ChemSpider 55493 YesY
ChEMBL CHEMBL279865 YesY
Synonyms 4-propionyloxy-4-phenyl-N-methylpiperidine, MPPP, 3-desmethylprodine
Chemical data
Formula C15H21NO2 
Mol. mass 247.33 g/mol
 YesY (what is this?)  (verify)

Desmethylprodine or 1-Methyl-4-phenyl-4-propionoxypiperidine (MPPP) is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche.[1] It is not used in clinical practice, but has been illegally manufactured for recreational drug use. Although it is an analog of Pethidine (Meperidine), the DEA has labeled it a Schedule I drug in the United States. As it is the reversed ester of pethidine, it is listed as having 70% of the potency of morphine.

History[edit]

1,3-Dimethyl-4-phenyl-4-propionoxypiperidine 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.[2] Ziering had been searching for synthetic pain-killers that were less addictive than morphine. The new drug was a slight variant of Demerol. It was found no more effective than Demerol, and was never marketed.[3]

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 Demerol'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 of Parkinson's disease and was hospitalized. Physicians were perplexed, since 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.[3][4]

Toxic impurity[edit]

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, MPTP was formed as a major impurity.[5]

1-Methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP, causes rapid onset of irreversible symptoms similar to Parkinson's Disease.[6][7] 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.[8]

Synthesis[edit]

U.S. Patent 2,765,315 Rohm and Haas (1956) Example 3.

Following example 1:

1-methyl-4-phenyl-4-acetoxypiperidine is product.

Analogues[edit]

More potent analogues can be made.

Different N-substituents on the piperidine ring other than 1-methyl group.

E.g. γ-phenylpropyl (637 x meperidine), cinnamyl (785 x meperidine),[9] γ-hydroxyl-γ-phenylpropyl

See here, Sterling-Winthrop bragging that they make analog 3219 x potency of meperidine.[10] The unreduced ketone was 1346 x meperidine.

Janssen already reported that 1-(3-phenyl-3-propionoxypropyl)-4-phenyl-4-propionoxypiperidine was ~3040 x meperidine in 1960.[11]

See also[edit]

External links[edit]

References[edit]

  1. ^ U.S. Patent 2,765,314 - Preparation of Esters
  2. ^ Ziering, A.; Lee, J. (1947). "Piperidine derivatives; 1,3-dialkyl-4-aryl-4-acyloxypiperidines". The Journal of Organic Chemistry 12 (6): 911–914. doi:10.1021/jo01170a024. PMID 18919744.  edit
  3. ^ a b Schwarcz, Joe (2005). "Aim high: synthetic opiates deliver surprising side effects". Canadian Chemical News 57 (10): 10. 
  4. ^ Gibb, Barry J. (2007). The Rough Guide to the Brain, Rough Guides Ltd., London, [1]
  5. ^ Johannessen, J. N.; Markey, S. P. (1984). "Assessment of the opiate properties of two constituents of a toxic illicit drug mixture". Drug and alcohol dependence 13 (4): 367–374. doi:10.1016/0376-8716(84)90004-8. PMID 6148225.  edit
  6. ^ Davis, G. C.; Williams, A. C.; Markey, S. P.; Ebert, M. H.; Caine, E. D.; Reichert, C. M.; Kopin, I. J. (1979). "Chronic Parkinsonism secondary to intravenous injection of meperidine analogues". Psychiatry Research 1 (3): 249–254. doi:10.1016/0165-1781(79)90006-4. PMID 298352.  edit
  7. ^ Wallis, Claudia (2001-06-24). "Surprising Clue to Parkinson's - TIME". Time. Retrieved 2010-05-13. 
  8. ^ Schmidt, N.; Ferger, B. (2001). "Neurochemical findings in the MPTP model of Parkinson's disease". Journal of neural transmission (Vienna, Austria : 1996) 108 (11): 1263–1282. doi:10.1007/s007020100004. PMID 11768626.  edit
  9. ^ 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. doi:10.1021/ja01551a038.  edit
  10. ^ Carabateas, P. M.; Grumbach, L. (1962). "Strong Analgesics. Some 1-Substituted 4-Phenyl-4-Propionoxypiperidines". Journal of Medicinal and Pharmaceutical Chemistry 5 (5): 913. doi:10.1021/jm01240a003.  edit
  11. ^ P. Janssen and N. B. Eddy, J. Med. Pharm. Chem., 2, 31 (1960).