Norpethidine

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Norpethidine
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Identifiers
  • Ethyl 4-phenylpiperidine-4-carboxylate
CAS Number
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Chemical and physical data
Formula C14H19NO2
Molar mass 233.311 g·mol−1
3D model (JSmol)
  • O=C(OCC)C2(c1ccccc1)CCNCC2
  • InChI=1S/C14H19NO2/c1-2-17-13(16)14(8-10-15-11-9-14)12-6-4-3-5-7-12/h3-7,15H,2,8-11H2,1H3 Yes check.svgY
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Norpethidine (normeperidine, pethidine intermediate B) is a 4-phenylpiperidine derivative that is both a precursor to, and the toxic metabolite of, pethidine (meperidine). It is scheduled by UN Single Convention on Narcotic Drugs. It is a Schedule II Narcotic controlled substance in the United States and has an ACSCN of 9233. The 2014 annual manufacturing quota was 11 grams (0.39 oz). [2]

Contents

Norpethidine is a controlled drug because of its potential uses in manufacturing both pethidine itself and a range of N-substituted derivatives, but it has little opioid activity in its own right. Instead, norpethidine acts as a stimulant and causes convulsions. [3] [4]

Bioaccumulation of norpethidine is a major complication when pethidine is used in medicine as an analgesic, as when pethidine is used in high doses [5] or administered by intravenous infusion, [6] norpethidine can accumulate in the body at a faster rate than it is being excreted, particularly in elderly patients [7] or those with compromised liver or kidney function, [8] resulting in a range of toxic effects, mainly convulsions, but also myoclonus [9] and hyponatremia. [10] These complications can be serious and have sometimes resulted in death. [11]

Metabolism of pethidine to norpethidine is carried out mainly by the CYP enzymes, CYP2B6, CYP2C19 and CYP3A4, in the liver, and since the activity of these enzymes can vary between individuals and can be influenced by concurrent use of other drugs, the rate and extent of norpethidine production can be difficult to predict. [12] [13]

Precursor Use

Norpethidine can be used as a precursor in synthesis of other drugs, including etoxeridine, [14] benzethidine, [15] furethidine, [16] morpheridine, anileridine, phenoperidine, piminodine, oxpheneridine, pheneridine & carperidine.

Legitimate research chemical uses include: R 951 [17] [18] [19] [20] R 1187, [21] R 1204, [21] [22] R 1133, [21] R 960 [21] PCP-hybrid (121019-93-0), [23] amitriptyline-hybrid.

See also

Related Research Articles

<span class="mw-page-title-main">Desmethylprodine</span> Opioid analgesic drug

Desmethylprodine or 1-methyl-4-phenyl-4-propionoxypiperidine is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. 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. 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.

<span class="mw-page-title-main">Pethidine</span> Opioid analgesic

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, in Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines, the prodines, bemidones, and others more distant, including diphenoxylate and analogues.

<span class="mw-page-title-main">Phenoperidine</span> Opioid analgesic drug

Phenoperidine, is an opioid analgesic which is structurally related to pethidine and is used clinically as a general anesthetic.

<span class="mw-page-title-main">Piritramide</span> Synthetic opioid

Piritramide(R-3365, trade names Dipidolor, Piridolan, Pirium and others) is a synthetic opioid analgesic that is marketed in certain European countries including: Austria, Belgium, Czech Republic, Slovenia, Germany and the Netherlands. It comes in free form, is about 0.75x times as potent as morphine and is given parenterally for the treatment of severe pain. Nausea, vomiting, respiratory depression and constipation are believed to be less frequent with piritramide than with morphine, and it produces more rapid-onset analgesia when compared to morphine and pethidine. After intravenous administration the onset of analgesia is as little as 1–2 minutes, which may be related to its great lipophilicity. The analgesic and sedative effects of piritramide are believed to be potentiated with phenothiazines and its emetic (nausea/vomiting-inducing) effects are suppressed. The volume of distribution is 0.7-1 L/kg after a single dose, 4.7-6 L/kg after steady-state concentrations are achieved and up to 11.1 L/kg after prolonged dosing.

<span class="mw-page-title-main">Dezocine</span> Opioid analgesic

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain. It is used by intravenous infusion and intramuscular injection.

<span class="mw-page-title-main">Prodine</span> Opioid analgesic

Prodine is an opioid analgesic that is an analog of pethidine (meperidine). It was developed in Germany in the late 1940s.

<span class="mw-page-title-main">Piminodine</span> Opioid analgesic drug

Piminodine (Alvodine) is an opioid analgesic that is an analogue of pethidine (meperidine). It was used in medicine briefly during the 1960s and 70s, but has largely fallen out of clinical use. It was used particularly for obstetric analgesia and in dental procedures and, like pethidine, could be combined with hydroxyzine to intensify the effects. The duration of action is 2–4 hours; 7.5–10 mg via the subcutaneous route is the most common starting dose, being equal to 80–100 mg of pethidine, 40–60 mg of alphaprodine and 10 mg of morphine. Oral formulations were also available.

<span class="mw-page-title-main">Ethoheptazine</span> Opioid analgesic drug

Ethoheptazine is an opioid analgesic from the phenazepane family. It was invented in the 1950s and is a ring expanded analogue of pethidine.

<span class="mw-page-title-main">Pethidinic acid</span> Chemical compound

Pethidinic acid is a 4-phenylpiperidine derivative that is both a metabolite of and a precursor to pethidine (meperidine). It is scheduled by UN Single Convention on Narcotic Drugs. It is a Schedule II Narcotic controlled substance in the United States and has an ACSCN of 9234. The 2014 annual manufacturing quota was 6 grams.

<span class="mw-page-title-main">Benzethidine</span> Chemical compound

Benzethidine is a 4-phenylpiperidine derivative that is related to the clinically used opioid analgesic drug pethidine.

<span class="mw-page-title-main">Furethidine</span> Chemical compound

Furethidine is a 4-phenylpiperidine derivative that is related to the clinically used opioid analgesic drug pethidine (meperidine), but with around 25x higher potency. According to another source, Furethidine is 500/30 = 16.7 x the potency of pethidine.

<span class="mw-page-title-main">Morpheridine</span> Chemical compound

Morpheridine (Morpholinoethylnorpethidine) is a 4-phenylpiperidine derivative that is related to the clinically used opioid analgesic drug pethidine (meperidine). It is a strong analgesic with around 4 times the potency of pethidine, and unlike pethidine, does not cause convulsions, although it produces the standard opioid side effects such as sedation and respiratory depression.

<span class="mw-page-title-main">Pheneridine</span> Chemical compound

Pheneridine is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine).

<span class="mw-page-title-main">Sameridine</span> Chemical compound

Sameridine is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine).

<span class="mw-page-title-main">PEPAP</span> Opioid analgesic drug

PEPAP (phenethylphenylacetoxypiperidine) is an opioid analgesic that is an analog of desmethylprodine.

<span class="mw-page-title-main">Pethidine intermediate A</span> Chemical compound

Pethidine intermediate A is a four-phenylpiperidine derivative that is a precursor to the opioid analgesic drug pethidine (meperidine). It is not known to have any analgesic activity in its own right, however other derivatives of pethidine with a 4-cyano group in place of the carboxylate ethyl ester have been found to be active, so pethidine intermediate A might also show opioid effects. It is scheduled by UN Single Convention on Narcotic Drugs. It is a Schedule II Narcotic controlled substance in the United States and has an ACSCN of 9232. The 2014 annual manufacturing quota was 6 grammes.

<span class="mw-page-title-main">Picenadol</span> Chemical compound

Picenadol (LY-97435) is a 4-phenylpiperidine derivative that is an opioid analgesic drug developed by Eli Lilly in the 1970s.

<span class="mw-page-title-main">Levallorphan</span> Opioid medication

Levallorphan, also known as levallorphan tartrate (USAN), is an opioid modulator of the morphinan family used as an opioid analgesic and opioid antagonist/antidote. It acts as an antagonist of the μ-opioid receptor (MOR) and as an agonist of the κ-opioid receptor (KOR), and as a result, blocks the effects of stronger agents with greater intrinsic activity such as morphine whilst simultaneously producing analgesia.

<span class="mw-page-title-main">4-Fluoropethidine</span> Chemical compound

4-Fluoropethidine is a drug that is a derivative of pethidine (meperidine), which combines pethidine's opioid analgesic effects with increased monoamine reuptake inhibition. It is around 50% less potent than pethidine as an opioid analgesic, but conversely is 50% more potent as a dopamine reuptake inhibitor, with other derivatives such as the 4-iodo and 3,4-dichloro analogues being even more potent dopamine reuptake inhibitors again. However, none of these compounds substitute for cocaine or produce stimulant effects in animals, suggesting that they still act primarily as opioid analgesic drugs in practice. Its action and degree of relation to pethidine means that it may be controlled in those countries which have laws about controlled-substance analogues; it is not itself listed in the Controlled Substances Act 1970.

<span class="mw-page-title-main">R1317</span> Pharmaceutical compound

R1317 is a desmethylprodine analog in which the N-methyl group is replaced by a cinnamyl group. This change in sidechain endows the compound with an increase in potency. The compound is 261 times more potent than meperidine in mice and 1100 times more potent in rats. In another article it was stated to be 785 times more potent than meperidine.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ "Conversion Factors for Controlled Substances". Diversion Control Division. Drug Enforcement Administration (DEA), U.S. Department of Justice.
  3. ↑ Umans JG, Inturrisi CE (October 1982). "Antinociceptive activity and toxicity of meperidine and normeperidine in mice". The Journal of Pharmacology and Experimental Therapeutics. 223 (1): 203–6. PMID   7120119.
  4. ↑ Plummer JL, Gourlay GK, Cmielewski PL, Odontiadis J, Harvey I (January 1995). "Behavioural effects of norpethidine, a metabolite of pethidine, in rats". Toxicology. 95 (1–3): 37–44. doi:10.1016/0300-483x(94)02871-q. PMID   7825188.
  5. ↑ Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS (January 2002). "Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction". Archives of Surgery. 137 (1). Chicago, Ill.: 84–8. doi: 10.1001/archsurg.137.1.84 . PMID   11772223.
  6. ↑ Stone PA, Macintyre PE, Jarvis DA (November 1993). "Norpethidine toxicity and patient controlled analgesia". British Journal of Anaesthesia. 71 (5): 738–40. doi: 10.1093/bja/71.5.738 . PMID   8251291.
  7. ↑ Holmberg L, Odar-Cederlof I, Boreus LO, Heyner L, Ehrnebo M. Comparative disposition of pethidine and norpethidine in old and young patients. European Journal of Clinical Pharmacology. 1982;22(2):175-9.
  8. ↑ Pond SM, Tong T, Benowitz NL, Jacob P, Rigod J (August 1981). "Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects". Clinical Pharmacology and Therapeutics. 30 (2): 183–8. doi:10.1038/clpt.1981.146. PMID   7249503. S2CID   10117158.
  9. ↑ Reutens DC, Stewart-Wynne EG (December 1989). "Norpethidine induced myoclonus in a patient with renal failure". Journal of Neurology, Neurosurgery, and Psychiatry. 52 (12): 1450–1. doi:10.1136/jnnp.52.12.1450. PMC   1031622 . PMID   2614458.
  10. ↑ Appel WC (November 1987). "Possible roles of normeperidine and hyponatremia in a postoperative death". Canadian Medical Association Journal. 137 (10): 912–3. PMC   1267380 . PMID   3676934.
  11. ↑ Jiraki K (March 1992). "Lethal effects of normeperidine". The American Journal of Forensic Medicine and Pathology. 13 (1): 42–3. doi:10.1097/00000433-199203000-00009. PMID   1585886. S2CID   32005631.
  12. ↑ Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ (September 2004). "CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 32 (9): 930–6. PMID   15319333.
  13. ↑ McHugh GJ (June 1999). "Norpethidine accumulation and generalized seizure during pethidine patient-controlled analgesia". Anaesthesia and Intensive Care. 27 (3): 289–91. PMID   10389564.
  14. ↑ USgranted 2858316,Henri M,"New piperidine derivatives",published 28 October 1958, assigned to UCB SA
  15. ↑ Frearson PM, Stern ES (1958). "622. Some new analogues of pethidine. Part III. 1-Aryloxy-alkylnorpethidines, and close analogues". Journal of the Chemical Society (Resumed): 3065–7. doi:10.1039/JR9580003065.
  16. ↑ Frearson PM, Hardy DG, Stern ES (1960). "426. Some new analogues of pethidine. Part IV. Substituents at the 1-position incorporating cyclic ether groups". Journal of the Chemical Society (Resumed): 2103–7. doi:10.1039/JR9600002103.
  17. ↑ Janssen, Paul A. J.; Jageneau, Anton H. M.; Demoen, Paul J. A.; Westeringh, Corn. van De.; Raeymaekers, Alfons H. M.; Wouters, Maria S. J.; Sanczuk, Stefan; Hermans, Bert K. F.; Loomans, Jozef L. M. (1959). "Compounds Related to Pethidine--I. Mannich Bases Derived from Norpethidine and Acetophenones". Journal of Medicinal and Pharmaceutical Chemistry. 1 (1): 105–120. doi:10.1021/jm50002a008.
  18. ↑ Janssen, Paul A. J.; Jageneau, Anton H. M.; Demoen, Paul J. A.; van De Westeringh, Corn.; De Canniere, Julienne H. M.; Raeymaekers, Alfons H. M.; Wouters, Maria S. J.; Sanczuk, Stefan; Hermans, Bert K. F. (2002). "Compounds Related to Pethidine--II. Mannich Bases Derived from Various Esters of 4-Carboxy-4-phenylpiperidine and Acetophenones". Journal of Medicinal and Pharmaceutical Chemistry. 1 (4): 309–317. doi:10.1021/jm50005a002.
  19. ↑ Pohland Albert, US2951080 (1960 to Eli Lilly and Co).
  20. ↑ Jr Frank A Cutler & James F Fisher, US2962501 (1960 to Merck and Co Inc).
  21. 1 2 3 4 Janssen, Paul; Jageneau, Anton H. M.; Demoen, Paul J. A.; van De Westeringh, Corn.; De Canniere, Julienne H. M.; Raeymaekers, Alfons H. M.; Wouters, Maria; Sanczuk, Stefan; Hermans, Bert K. F. (1960). "Compounds Related to Pethidine--III. Basic Ketones derived from Norpethidine". Journal of Medicinal and Pharmaceutical Chemistry. 2 (3): 271–280. doi:10.1021/jm50010a003.
  22. ↑ Elpern Bill, US3093652 (1963 to STWB Inc).
  23. ↑ Itzhak Y, Kalir A, Weissman BA, Cohen S. New analgesic drugs derived from phencyclidine. J Med Chem. 1981 May;24(5):496-9. doi: 10.1021/jm00137a004. PMID: 7241506.
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