Noscapine

Overview

Noscapine, also known as narcotine, nectodon, nospen, anarcotine and (archaic) opiane, is a benzylisoquinoline alkaloid of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the Papaveraceae (poppy) family. It lacks effects associated with opioids such as sedation, euphoria, or analgesia (pain-relief) and lacks addictive potential. Noscapine is primarily used for its antitussive (cough-suppressing) effects.[1] WP

Uses, dosage and effects

Medical uses

Noscapine is often used as an antitussive medication. A 2012 Dutch guideline, however, does not recommend its use for acute coughing.[2][3] WP

Recreational use

There are anecdotal reports of the recreational use of over-the-counter drugs in several countries, being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 minutes after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist.[4][5] WP

Anti-inflammatory effects

Various studies have indicated that noscapine has anti-inflammatory effects and significantly reduces the levels of proinflammatory factors such as interleukin 1β (IL-1β), IFN-c, and IL-6. In this regard, in another study, Khakpour et al. examined the effect of noscapine against carrageenan-induced inflammation in rats. They found that noscapine at a dose of 5 mg/kg body weight in three hours after the injection has the most anti-inflammatory effects. Moreover, they showed that the amount of inflammation reduction at this dose of noscapine is approximately equal to indomethacin, a standard anti-inflammatory medication. Furthermore, Shiri et al. concluded that noscapine prevented the progression of bradykinin-induced inflammation in the rat's foot by antagonising bradykinin receptors. In addition, Zughaier et al. evaluated the anti-inflammatory effects of brominated noscapine. The brominated form of noscapine has been shown to inhibit the secretion of the cytokine TNF-α and the chemokine CXCL10 from macrophages, thereby reducing inflammation without affecting macrophage survival. Furthermore, the bromated derivative of noscapine has about 5 to 40 times more potent effects than noscapine. Again, this brominated derivative also inhibits toll-like receptors (TLR), TNF-α, and nitric oxide (NO) in human and mouse macrophages without causing toxicity. WP

Risks and side effects

Side effects

• Nausea WP
• Vomiting WP
• Loss of coordination WP
• Hallucinations (auditory and visual) WP
• Loss of sexual drive WP
• Swelling of prostate WP
• Loss of appetite WP
• Dilated pupils WP
• Increased heart rate WP
• Shaking and muscle spasms WP
• Chest pain WP
• Increased alertness WP
• Increased wakefulness WP
• Loss of stereoscopic vision WP

Interactions

Interactions

Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics.[6] WP

The drug should not be taken with monoamine oxidase inhibitors (MAOIs), as unknown and potentially fatal effects may occur. WP⚠ Wikipedia itself has flagged this text: citation needed.

Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased.[7] WP

Pharmacology

Mechanism of action

Noscapine's antitussive effects appear to be primarily mediated by its σ–receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment with rimcazole, a σ-specific antagonist, causes a dose-dependent reduction in antitussive activity of noscapine. Noscapine, and its synthetic derivatives called noscapinoids, are known to interact with microtubules and inhibit cancer cell proliferation[8][9] WP

Research

Clinical trials

The efficacy of noscapine in the treatment of certain hematological malignancies has been explored in the clinic. Polyploidy induction by noscapine has been observed in vitro in human lymphocytes at high dose levels (>30 μM); however, low-level systemic exposure, e.g. with cough medications, does not appear to present a genotoxic hazard. The mechanism of polyploidy induction by noscapine is suggested to involve either chromosome spindle apparatus damage or cell fusion.[10–13] WP

Noscapine biosynthesis reconstitution

Many of the enzymes in the noscapine biosynthetic pathway was elucidated by the discovery of a 10 gene "operon-like cluster" named HN1. In 2016, the biosynthetic pathway of noscapine was reconstituted in yeast cells, allowing the drug to be synthesised without the requirement of harvest and purification from plant material. In 2018, the entire noscapine pathway was reconstituted and produced in yeast from simple molecules. In addition, protein expression was optimised in yeast, allowing production of noscapine to be improved 18,000 fold. It is hoped that this technology could be used to produce pharmaceutical alkaloids such as noscapine which are currently expressed at too low a yield in plantae to be mass-produced, allowing them to become marketable therapeutic drugs.[14–17] WP

Anticancer derivatives

Noscapine is itself an antimitotic agent, therefore its analogs have great potential as novel anti-cancer drugs. Analogs having significant cytotoxic effects through modified 1,3-benzodioxole moiety have been developed. Similarly, N-alkyl amine, 1,3-diynyl, 9-vinyl-phenyl and 9-arylimino derivatives of noscapine have also been developed. Their mechanism of action is through tubulin inhibition.[18–24] WP

History

History

Noscapine was first isolated and characterized in chemical breakdown and properties in 1803 under the denomination of "Narcotine" by Jean-François Derosne, a French chemist in Paris. In 1817, Pierre-Jean Robiquet, another French chemist, reinvestigated the substance and named it "Narcotine". He proved narcotine and morphine to be distinct alkaloids in 1831. Finally, Pierre-Jean Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, currently a widely used opium-derived compound.[25–28] WP

Legal status

Noscapine in heroin

Noscapine can survive the manufacturing processes of heroin and can be found in street heroin. This is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Liège, Belgium, the average noscapine concentration was around 8%.[29] WP

Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine. Since the diamorphine in street heroin is the same as the pharmaceutical diamorphine, examination of the contaminants is the only way to test whether street heroin has been used. Other contaminants used in urine samples alongside noscapine include papaverine and acetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites, cotarnine and meconine. Detection is performed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry (LCMS) but can also use a variety of other analytical techniques.[30] WP

Chemistry

Formula

C22H23NO7 PC

Molar mass (g/mol)

413.4 PC

IUPAC name (computed by PubChem)

(3S)-6,7-dimethoxy-3-[(5R)-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-3H-2-benzofuran-1-one PC

SMILES

CN1CCC2=CC3=C(C(=C2[C@@H]1[C@@H]4C5=C(C(=C(C=C5)OC)OC)C(=O)O4)OC)OCO3 PC

InChIKey

AKNNEGZIBPJZJG-MSOLQXFVSA-N PC

PubChem CID

275196

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Altinoz MA, Topcu G, Hacimuftuoglu A, Ozpinar A, Ozpinar A, Hacker E, Elmaci İ. Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma. Neurochemical Research. August 2019. doi:10.1007/s11064-019-02837-x · PMID 31292803
2. Journal / agency Singh H, Singh P, Kumari K, Chandra A, Dass SK, Chandra R. A review on noscapine, and its impact on heme metabolism. Current Drug Metabolism. March 2013. doi:10.2174/1389200211314030010 · PMID 22935070
3. Journal / agency Verlee L, Verheij TJ, Hopstaken RM, Prins JM, Salomé PL, Bindels PJ. Summary of NHG practice guideline 'Acute cough'. Nederlands Tijdschrift voor Geneeskunde. 2012. PMID 22917039
4. Journal / agency Bhatia M, Vaid L. Type of drug abuse in patients with psychogenic cough. The Journal of Laryngology and Otology. August 2004. doi:10.1258/0022215041917844 · PMID 15453951
5. Journal / agency Church J, Jones MG, Davies SN, Lodge D. Antitussive agents as N-methylaspartate antagonists: further studies. Canadian Journal of Physiology and Pharmacology. June 1989. doi:10.1139/y89-090 · PMID 2673498
6. Other Austria-Codex. 2007
7. Journal / agency Ohlsson S, Holm L, Myrberg O, Sundström A, Yue QY. Noscapine may increase the effect of warfarin. British Journal of Clinical Pharmacology. February 2008. doi:10.1111/j.1365-2125.2007.03018.x · PMID 17875192 · PMC2291222
8. Journal / agency Kamei J. Role of opioidergic and serotonergic mechanisms in cough and antitussives. Pulmonary Pharmacology. 1996. doi:10.1006/pulp.1996.0046 · PMID 9232674
9. Journal / agency Lopus M, Naik PK. Taking aim at a dynamic target: Noscapinoids as microtubule-targeted cancer therapeutics. Pharmacological Reports. February 2015. doi:10.1016/j.pharep.2014.09.003 · PMID 25560576
10. Other Study of Noscapine for Patients With Low Grade Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia Refractory to Chemotherapy. May 22, 2014
11. Other A Study of Noscapine HCl (CB3304) in Patients with Relapsed or Refractory Multiple Myeloma. October 7, 2016
12. Journal / agency Mitchell ID, Carlton JB, Chan MY, Robinson A, Sunderland J. Noscapine-induced polyploidy in vitro. Mutagenesis. November 1991. doi:10.1093/mutage/6.6.479 · PMID 1800895
13. Journal / agency Schuler M, Muehlbauer P, Guzzie P, Eastmond DA. Noscapine hydrochloride disrupts the mitotic spindle in mammalian cells and induces aneuploidy as well as polyploidy in cultured human lymphocytes. Mutagenesis. January 1999. doi:10.1093/mutage/14.1.51 · PMID 10474821
14. Journal / agency Winzer T, Gazda V, He Z, Kaminski F, Kern M, Larson TR, Li Y, Meade F, Teodor R, Vaistij FE, Walker C, Bowser TA, Graham IA. A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine. Science. June 2012. doi:10.1126/science.1220757 · PMID 22653730
15. Journal / agency Li Y, Smolke CD. Engineering biosynthesis of the anticancer alkaloid noscapine in yeast. Nature Communications. July 2016. doi:10.1038/ncomms12137 · PMID 27378283 · PMC4935968
16. Journal / agency Li Y, Li S, Thodey K, Trenchard I, Cravens A, Smolke CD. Complete biosynthesis of noscapine and halogenated alkaloids in yeast. Proceedings of the National Academy of Sciences of the United States of America. April 2018. doi:10.1073/pnas.1721469115 · PMID 29610307 · PMC5924921
17. Journal / agency Kries H, O'Connor SE. Biocatalysts from alkaloid producing plants. Current Opinion in Chemical Biology. April 2016. doi:10.1016/j.cbpa.2015.12.006 · PMID 26773811
18. Journal / agency Mahmoudian M, Rahimi-Moghaddam P. The anti-cancer activity of noscapine: a review. Recent Patents on Anti-Cancer Drug Discovery. January 2009. doi:10.2174/157489209787002524 · PMID 19149691
19. Journal / agency Yong C, Devine SM, Abel AC, Tomlins SD, Muthiah D, Gao X, Callaghan R, Steinmetz MO, Prota AE, Capuano B, Scammells PJ. 1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure. ChemMedChem. September 2021. doi:10.1002/cmdc.202100363 · PMID 34159741
20. Journal / agency Dash SG, Suri C, Nagireddy PK, Kantevari S, Naik PK. Rational design of 9-vinyl-phenyl noscapine as potent tubulin binding anticancer agent and evaluation of the effects of its combination on Docetaxel. Journal of Biomolecular Structure & Dynamics. September 2021. doi:10.1080/07391102.2020.1785945 · PMID 32608323
21. Journal / agency Meher RK, Pragyandipta P, Pedapati RK, Nagireddy PK, Kantevari S, Nayek AK, Naik PK. Rational design of novel N-alkyl amine analogues of noscapine, their chemical synthesis and cellular activity as potent anticancer agents. Chemical Biology & Drug Design. September 2021. doi:10.1111/cbdd.13901 · PMID 34051055
22. Journal / agency Patel AK, Meher RK, Reddy PK, Pedapati RK, Pragyandipta P, Kantevari S, Naik MR, Naik PK. Rational design, chemical synthesis and cellular evaluation of novel 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents. Journal of Molecular Graphics & Modelling. July 2021. doi:10.1016/j.jmgm.2021.107933 · PMID 33991960
23. Journal / agency Patel AK, Meher RK, Nagireddy PK, Pragyandipta P, Pedapati RK, Kantevari S, Naik PK. 9-Arylimino noscapinoids as potent tubulin binding anticancer agent: chemical synthesis and cellular evaluation against breast tumour cells. SAR and QSAR in Environmental Research. April 2021. doi:10.1080/1062936X.2021.1891567 · PMID 33687299
24. Journal / agency Mandavi S, Verma SK, Banjare L, Dubey A, Bhatt R, Thareja S, Jain AK. A Comprehension into Target Binding and Spatial Fingerprints of Noscapinoid Analogues as Inhibitors of Tubulin. Medicinal Chemistry. 2021. doi:10.2174/1573406416666200117120348 · PMID 31951171
25. Journal / agency Derosne JF. Mémoire sur l'opium. Annales de chimie. 1803
26. Journal / agency Drobnik J, Drobnik E. Timeline and bibliography of early isolations of plant metabolites (1770-1820) and their impact to pharmacy: A critical study. Fitoterapia. December 2016. doi:10.1016/j.fitote.2016.10.009 · PMID 27984164
27. Journal / agency Usselman M, Rocke A, Reinhart C, Foulser K. Restaging Liebig: A Study in the Replication of Experiments. Annals of Science. January 2005. doi:10.1080/00033790410001711922
28. Journal / agency Wisniak J. Pierre-Jean Robiquet. Educación Química. March 2013. doi:10.1016/S0187-893X(13)72507-2
29. Journal / agency Denooz R, Dubois N, Charlier C. Analysis of two year heroin seizures in the Liege area. Revue Médicale de Liège. September 2005. PMID 16265967
30. Journal / agency Paterson S, Lintzeris N, Mitchell TB, Cordero R, Nestor L, Strang J. Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence. Addiction. December 2005. doi:10.1111/j.1360-0443.2005.01225.x · PMID 16367984

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.