Not to be confused with MαPPP (stimulant designer drug), MPTP (neurotoxic impurity of desmethylprodine synthesis) or MPP+ (neurotoxic metabolite of MPTP).
Desmethylprodine or 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP, Ro 2-0718) is an opioidanalgesic 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 was not reported to 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]
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 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 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. It was later found that his development of Parkinson's was due to a common impurity in the synthesis of MPPP called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that specifically targets dopamine producing neurons.[4][5]
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.[6] It is listed under the Single Convention on Narcotic Drugs and is controlled in most countries in the same fashion as is morphine.
Toxic impurityedit
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.[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]
^US 2765314, Schmidle CJ, Mansfield RC, "Preparation of Esters", issued 2 October 1956, assigned to Rohm and Haas
^ abcReynolds AK, Randall LO (1957). Morphine & Allied Drugs. p. 310.
^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.
^ abSchwarcz J (2005). "Aim high: synthetic opiates deliver surprising side effects". Canadian Chemical News. 57 (10): 10.
^Gibb BJ (2007). The Rough Guide to the Brain. London: Rough Guides Ltd. p. 166. ISBN978-1-4093-5993-7.
^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. PMID 6148225.
^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.
^Wallis C (2001-06-24). . Time. Archived from the original on February 11, 2007. Retrieved 2010-05-13.
^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.
^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.
^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.
^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.
External linksedit
Desmethylprodine - PubChem
Street-Drug Contaminant causing Parkinsonism - June 22, 1984 warning from the CDC regarding MPTP byproduct in MPPP
November 13, 2023
desmethylprodine, mppp, redirects, here, other, uses, mppp, disambiguation, confused, with, mαppp, stimulant, designer, drug, mptp, neurotoxic, impurity, desmethylprodine, synthesis, neurotoxic, metabolite, mptp, methyl, phenyl, propionoxypiperidine, mppp, 071. MPPP redirects here For other uses see MPPP disambiguation Not to be confused with MaPPP stimulant designer drug MPTP neurotoxic impurity of desmethylprodine synthesis or MPP neurotoxic metabolite of MPTP 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 was not reported to 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 DesmethylprodineClinical dataOther names4 propionyloxy 4 phenyl N methylpiperidine MPPP 3 desmethylprodineLegal statusLegal statusBR Class F1 Prohibited narcotics DE Anlage I Authorized scientific use only US Schedule IIdentifiersIUPAC name 1 Methyl 4 phenylpiperidin 4 yl propanoateCAS Number13147 09 6PubChem CID61583DrugBankDB01478 YChemSpider55493 YUNII07SGC963IRChEMBLChEMBL279865 YCompTox Dashboard EPA DTXSID80157061Chemical and physical dataFormulaC 15H 21N O 2Molar mass247 338 g mol 13D model JSmol Interactive imageSMILES O C CC OC1 CCN CC1 C C2 CC CC C2InChI 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 2H3 YKey BCQMRZRAWHNSBF UHFFFAOYSA N Y verify Contents 1 History 1 1 Toxic impurity 2 Analogs 3 See also 4 References 5 External linksHistory editDesmethylprodine 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 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 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 It was later found that his development of Parkinson s was due to a common impurity in the synthesis of MPPP called MPTP 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine a neurotoxin that specifically targets dopamine producing neurons 4 5 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 6 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 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 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 editStructural 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 editNorpethidine PEPAPReferences edit US 2765314 Schmidle CJ Mansfield RC Preparation of Esters issued 2 October 1956 assigned to Rohm and Haas a b c Reynolds AK Randall LO 1957 Morphine amp Allied Drugs p 310 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 a b Schwarcz J 2005 Aim high synthetic opiates deliver surprising side effects Canadian Chemical News 57 10 10 Gibb BJ 2007 The Rough Guide to the Brain London Rough Guides Ltd p 166 ISBN 978 1 4093 5993 7 Quotas 2014 DEA Diversion Control Division 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 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 Wallis C 2001 06 24 Surprising Clue to Parkinson s Time Archived from the original on February 11 2007 Retrieved 2010 05 13 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 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 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 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 External links editDesmethylprodine PubChem Street Drug Contaminant causing Parkinsonism June 22 1984 warning from the CDC regarding MPTP byproduct in MPPP Retrieved from https en wikipedia org w index php title Desmethylprodine amp oldid 1183506237, wikipedia, wiki, book, books, library,
