Noscapine

Noscapine is often used as an antitussive medication.{{cite journal | vauthors = Singh H, Singh P, Kumari K, Chandra A, Dass SK, Chandra R | title = A review on noscapine, and its impact on heme metabolism | journal = Current Drug Metabolism | volume = 14 | issue = 3 | pages = 351–360 | date = March 2013 | pmid = 22935070 | doi = 10.2174/1389200211314030010 }} A 2012 Dutch guideline, however, does not recommend its use for acute coughing.{{cite journal | vauthors = Verlee L, Verheij TJ, Hopstaken RM, Prins JM, Salomé PL, Bindels PJ | title = [Summary of NHG practice guideline 'Acute cough'] | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 156 | pages = A4188 | date = 2012 | pmid = 22917039 }}

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

Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics.{{cite book|title=Austria-Codex|editor=Jasek, W|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=2007/2008|isbn=978-3-85200-181-4|language=de}}

The drug should not be taken with monoamine oxidase inhibitors (MAOIs), as unknown and potentially fatal effects may occur.{{citation needed|date=February 2012}}

Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased.{{cite journal | vauthors = Ohlsson S, Holm L, Myrberg O, Sundström A, Yue QY | title = Noscapine may increase the effect of warfarin | journal = British Journal of Clinical Pharmacology | volume = 65 | issue = 2 | pages = 277–278 | date = February 2008 | pmid = 17875192 | pmc = 2291222 | doi = 10.1111/j.1365-2125.2007.03018.x }}

File:Noscapine Biosynthesis.tif

The biosynthesis of noscapine in P. somniferum begins with chorismic acid, which is synthesized via the shikimate pathway from erythrose 4-phosphate and phosphoenolpyruvate. Chorismic acid is a precursor to the amino acid tyrosine, the source of nitrogen in benzylisoquinoline alkaloids. Tyrosine can undergo a PLP-mediated transamination to form 4-hydroxyphenylpyruvic acid (4-HPP), followed by a TPP-mediated decarboxylation to form 4-hydroxyphenylacetaldehyde (4-HPAA). Tyrosine can also be hydroxylated to form 3,4-dihydroxyphenylalanine (DOPA), followed by a PLP-mediated decarboxylation to form dopamine. Norcoclaurine synthase (NCS) catalyzes a Pictet-Spengler reaction between 4-HPAA and dopamine to synthesize (S)-norcoclaurine, providing the characteristic benzylisoquinoline scaffold. (S)-Norcoclaurine is sequentially 6-O-methylated (6OMT), N-methylated (CNMT), 3-hydroxylated (NMCH), and 4′-O-methylated (4′OMT), with the use of cofactors S-adenosyl-methionine (SAM) and NADP⁺ for methylations and hydroxylations, respectively. These reactions produce (S)-reticuline, a key branchpoint intermediate in the biosynthesis of benzylisoquinoline alkaloids.{{cite journal | vauthors = Singh A, Menéndez-Perdomo IM, Facchini PJ | title=Benzylisoquinoline alkaloid biosynthesis in opium poppy: an update | journal=Phytochemistry Reviews | year=2019 | volume=18 | issue=6 | pages=1457–1482 | doi=10.1007/s11101-019-09644-w| bibcode=2019PChRv..18.1457S | s2cid=208301912 }}

The remainder of the noscapine biosynthetic pathway is largely governed by a single biosynthetic 10-gene cluster. Genes comprising the cluster encode enzymes responsible for nine of the eleven remaining chemical transformations. First, berberine bridge enzyme (BBE), an enzyme not encoded by the cluster, forms the fused four-ring structure in (S)-scoulerine. BBE uses O₂ as an oxidant and is aided by cofactor flavin adenine dinucleotide (FAD). Next, an O-methyltransferase (SOMT) methylates the 9-hydroxyl group. Canadine synthase (CAS) catalyzes the formation of a unique C2-C3 methylenedioxy bridge in (S)-canadine.{{cite journal | vauthors = Dang TT, Facchini PJ | title = Cloning and characterization of canadine synthase involved in noscapine biosynthesis in opium poppy | journal = FEBS Letters | volume = 588 | issue = 1 | pages = 198–204 | date = January 2014 | pmid = 24316226 | doi = 10.1016/j.febslet.2013.11.037 | bibcode = 2014FEBSL.588..198D | s2cid = 26504234 }} An N-methylation (TNMT) and two hydroxylations (CYP82Y1, CYP82X2) follow, aided by SAM and O₂/NADPH, respectively. The C13 alcohol is then acetylated by an acetyltransferase (AT1) using acetyl-CoA. Another cytochrome P450 enzyme (CYP82X1) catalyzes the hydroxylation of C8, and the newly formed hemiaminal spontaneously cleaves, yielding a tertiary amine and aldehyde. A methyltransferase heterodimer (OMT2:OMT3) catalyzes a SAM-mediated O-methylation on C4′.{{cite journal | vauthors = Park MR, Chen X, Lang DE, Ng KK, Facchini PJ | title = Heterodimeric O-methyltransferases involved in the biosynthesis of noscapine in opium poppy | journal = The Plant Journal | volume = 95 | issue = 2 | pages = 252–267 | date = July 2018 | pmid = 29723437 | doi = 10.1111/tpj.13947 | s2cid = 19237801 | doi-access = free }} The O-acetyl group is then cleaved by a carboxylesterase (CXE1), yielding an alcohol which immediately reacts with the neighboring C1 aldehyde to form a hemiacetal in a new five-membered ring. The apparent counteractivity between AT1 and CXE1 suggests that acetylation in this context is employed as a protective group, preventing hemiacetal formation until the ester is enzymatically cleaved.{{cite journal | vauthors = Dang TT, Chen X, Facchini PJ | title = Acetylation serves as a protective group in noscapine biosynthesis in opium poppy | journal = Nature Chemical Biology | volume = 11 | issue = 2 | pages = 104–106 | date = February 2015 | pmid = 25485687 | doi = 10.1038/nchembio.1717 }} Finally, an NAD⁺-dependent short-chain dehydrogenase (NOS) oxidizes the hemiacetal to a lactone, completing noscapine biosynthesis.

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.{{cite journal | vauthors = Kamei J | title = Role of opioidergic and serotonergic mechanisms in cough and antitussives | journal = Pulmonary Pharmacology | volume = 9 | issue = 5–6 | pages = 349–356 | year = 1996 | pmid = 9232674 | doi = 10.1006/pulp.1996.0046 }} Noscapine, and its synthetic derivatives called noscapinoids, are known to interact with microtubules and inhibit cancer cell proliferation {{cite journal | vauthors = Lopus M, Naik PK | title = Taking aim at a dynamic target: Noscapinoids as microtubule-targeted cancer therapeutics | journal = Pharmacological Reports | volume = 67 | issue = 1 | pages = 56–62 | date = February 2015 | pmid = 25560576 | doi = 10.1016/j.pharep.2014.09.003 | s2cid = 19622488 }}

The lactone ring is unstable and opens in basic media. The opposite reaction is presented in acidic media. The bond (C1−C3′) connecting the two optically active carbon atoms is also unstable. In aqueous solution of sulfuric acid and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with zinc/HCl, the bond C1−C3′ saturates and the molecule dissociates into hydrocotarnine (2-hydroxycotarnine) and meconine (6,7-dimethoxyisobenzofuran-1(3H)-one).

Noscapine was first isolated and characterized in chemical breakdown and properties in 1803 under the denomination of "Narcotine"{{cite journal | vauthors = Derosne JF | title = Mémoire sur l'opium. | journal = Annales de chimie | date = 1803 | volume = 11| pages = 257–285 | url = https://cir.nii.ac.jp/crid/1573387449769822464 }}{{cite journal | vauthors = Drobnik J, Drobnik E | title = Timeline and bibliography of early isolations of plant metabolites (1770-1820) and their impact to pharmacy: A critical study | journal = Fitoterapia | volume = 115 | issue = | pages = 155–164 | date = December 2016 | pmid = 27984164 | doi = 10.1016/j.fitote.2016.10.009 }} by Jean-Francois Derosne, a French chemist in Paris. Then Pierre-Jean Robiquet, another French chemist, proved narcotine and morphine to be distinct alkaloids in 1831.{{cite journal | vauthors = Wisniak J | title = Pierre-Jean Robiquet | journal = Educación Química | date = March 2013 | volume = 24 | issue = Supplement 1 | pages = 139–149 | doi = 10.1016/S0187-893X(13)72507-2 | doi-access = free }} 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.

There are anecdotal reports of the recreational use of over-the-counter drugs in several countries,{{cite journal | vauthors = Bhatia M, Vaid L | title = Type of drug abuse in patients with psychogenic cough | journal = The Journal of Laryngology and Otology | volume = 118 | issue = 8 | pages = 659–660 | date = August 2004 | pmid = 15453951 | doi = 10.1258/0022215041917844 | doi-access = free }} 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.{{cite journal | vauthors = Church J, Jones MG, Davies SN, Lodge D | title = Antitussive agents as N-methylaspartate antagonists: further studies | journal = Canadian Journal of Physiology and Pharmacology | volume = 67 | issue = 6 | pages = 561–567 | date = June 1989 | pmid = 2673498 | doi = 10.1139/y89-090 }}

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%.{{cite journal | vauthors = Denooz R, Dubois N, Charlier C | title = [Analysis of two year heroin seizures in the Liege area] | language = fr | journal = Revue Médicale de Liège | volume = 60 | issue = 9 | pages = 724–728 | date = September 2005 | pmid = 16265967 }}

Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine.{{cite journal | vauthors = Paterson S, Lintzeris N, Mitchell TB, Cordero R, Nestor L, Strang J | title = Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence | journal = Addiction | volume = 100 | issue = 12 | pages = 1832–1839 | date = December 2005 | pmid = 16367984 | doi = 10.1111/j.1360-0443.2005.01225.x | doi-access = free }} 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.

The efficacy of noscapine in the treatment of certain hematological malignancies has been explored in the clinic.{{Cite journal|url=https://clinicaltrials.gov/ct2/show/NCT00183950?term=noscapine&rank=2|title=Study of Noscapine for Patients With Low Grade Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia Refractory to Chemotherapy|date=May 22, 2014|website=ClinicalTrials.gov}}{{Cite journal|url=https://clinicaltrials.gov/ct2/show/NCT00912899?term=noscapine&rank=1|title=A Study of Noscapine HCl (CB3304) in Patients with Relapsed or Refractory Multiple Myeloma|date=October 7, 2016|website=ClinicalTrials.gov}} 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.{{cite journal | vauthors = Mitchell ID, Carlton JB, Chan MY, Robinson A, Sunderland J | title = Noscapine-induced polyploidy in vitro | journal = Mutagenesis | volume = 6 | issue = 6 | pages = 479–486 | date = November 1991 | pmid = 1800895 | doi = 10.1093/mutage/6.6.479 }}{{cite journal | vauthors = Schuler M, Muehlbauer P, Guzzie P, Eastmond DA | title = Noscapine hydrochloride disrupts the mitotic spindle in mammalian cells and induces aneuploidy as well as polyploidy in cultured human lymphocytes | journal = Mutagenesis | volume = 14 | issue = 1 | pages = 51–56 | date = January 1999 | pmid = 10474821 | doi = 10.1093/mutage/14.1.51 | doi-access = free }}

Many of the enzymes in the noscapine biosynthetic pathway was elucidated by the discovery of a 10 gene "operon-like cluster" named HN1.{{cite journal | vauthors = 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 | display-authors = 6 | title = A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine | journal = Science | volume = 336 | issue = 6089 | pages = 1704–1708 | date = June 2012 | pmid = 22653730 | doi = 10.1126/science.1220757 | s2cid = 41420733 | bibcode = 2012Sci...336.1704W | doi-access = free }} In 2016, the biosynthetic pathway of noscapine was reconstituted in yeast cells,{{cite journal | vauthors = Li Y, Smolke CD | title = Engineering biosynthesis of the anticancer alkaloid noscapine in yeast | journal = Nature Communications | volume = 7 | pages = 12137 | date = July 2016 | pmid = 27378283 | pmc = 4935968 | doi = 10.1038/ncomms12137 | bibcode = 2016NatCo...712137L }} 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.{{cite journal | vauthors = Li Y, Li S, Thodey K, Trenchard I, Cravens A, Smolke CD | title = Complete biosynthesis of noscapine and halogenated alkaloids in yeast | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 17 | pages = E3922–E3931 | date = April 2018 | pmid = 29610307 | pmc = 5924921 | doi = 10.1073/pnas.1721469115 | bibcode = 2018PNAS..115E3922L | doi-access = free }} 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.{{cite journal | vauthors = Kries H, O'Connor SE | title = Biocatalysts from alkaloid producing plants | journal = Current Opinion in Chemical Biology | volume = 31 | pages = 22–30 | date = April 2016 | pmid = 26773811 | doi = 10.1016/j.cbpa.2015.12.006 | doi-access = free | hdl = 21.11116/0000-0002-B92F-A | hdl-access = free }}

Noscapine is itself an antimitotic agent, therefore its analogs have great potential as novel anti-cancer drugs.{{cite journal | vauthors = Mahmoudian M, Rahimi-Moghaddam P | title = The anti-cancer activity of noscapine: a review | journal = Recent Patents on Anti-Cancer Drug Discovery | volume = 4 | issue = 1 | pages = 92–97 | date = January 2009 | pmid = 19149691 | doi = 10.2174/157489209787002524 }} Analogs having significant cytotoxic effects through modified 1,3-benzodioxole moiety have been developed.{{cite journal | vauthors = Yong C, Devine SM, Abel AC, Tomlins SD, Muthiah D, Gao X, Callaghan R, Steinmetz MO, Prota AE, Capuano B, Scammells PJ | display-authors = 6 | title = 1,3-Benzodioxole-Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin-Bound Structure | journal = ChemMedChem | volume = 16 | issue = 18 | pages = 2882–2894 | date = September 2021 | pmid = 34159741 | doi = 10.1002/cmdc.202100363 | s2cid = 235610355 }} Similarly, N-alkyl amine, 1,3-diynyl, 9-vinyl-phenyl and 9-arylimino derivatives of noscapine have also been developed.{{cite journal | vauthors = Dash SG, Suri C, Nagireddy PK, Kantevari S, Naik PK | title = Rational design of 9-vinyl-phenyl noscapine as potent tubulin binding anticancer agent and evaluation of the effects of its combination on Docetaxel | journal = Journal of Biomolecular Structure & Dynamics | volume = 39 | issue = 14 | pages = 5276–5289 | date = September 2021 | pmid = 32608323 | doi = 10.1080/07391102.2020.1785945 | s2cid = 220283865 | url = https://figshare.com/articles/journal_contribution/12844849 }}{{cite journal | vauthors = Meher RK, Pragyandipta P, Pedapati RK, Nagireddy PK, Kantevari S, Nayek AK, Naik PK | title = Rational design of novel N-alkyl amine analogues of noscapine, their chemical synthesis and cellular activity as potent anticancer agents | journal = Chemical Biology & Drug Design | volume = 98 | issue = 3 | pages = 445–465 | date = September 2021 | pmid = 34051055 | doi = 10.1111/cbdd.13901 | s2cid = 235243148 }}{{cite journal | vauthors = Patel AK, Meher RK, Reddy PK, Pedapati RK, Pragyandipta P, Kantevari S, Naik MR, Naik PK | display-authors = 6 | title = Rational design, chemical synthesis and cellular evaluation of novel 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents | journal = Journal of Molecular Graphics & Modelling | volume = 106 | issue = | pages = 107933 | date = July 2021 | pmid = 33991960 | doi = 10.1016/j.jmgm.2021.107933 | s2cid = 234683080 }}{{cite journal | vauthors = Patel AK, Meher RK, Nagireddy PK, Pragyandipta P, Pedapati RK, Kantevari S, Naik PK | title = 9-Arylimino noscapinoids as potent tubulin binding anticancer agent: chemical synthesis and cellular evaluation against breast tumour cells | journal = SAR and QSAR in Environmental Research | volume = 32 | issue = 4 | pages = 269–291 | date = April 2021 | pmid = 33687299 | doi = 10.1080/1062936X.2021.1891567 | bibcode = 2021SQER...32..269P | s2cid = 232161419 | url = https://figshare.com/articles/journal_contribution/14186036 | url-access = subscription }} Their mechanism of action is through tubulin inhibition.{{cite journal | vauthors = Mandavi S, Verma SK, Banjare L, Dubey A, Bhatt R, Thareja S, Jain AK | title = A Comprehension into Target Binding and Spatial Fingerprints of Noscapinoid Analogues as Inhibitors of Tubulin | journal = Medicinal Chemistry | volume = 17 | issue = 6 | pages = 611–622 | date = 2021 | pmid = 31951171 | doi = 10.2174/1573406416666200117120348 | s2cid = 210701250 }}

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.

• Cough syrup
• Codeine; Pholcodine
• Dextromethorphan; Dimemorfan
• Racemorphan; Dextrorphan; Levorphanol
• Butamirate
• Pentoxyverine
• Tipepidine
• Cloperastine
• Levocloperastine
• Narceine, a related opium alkaloid.

{{Reflist|2}}

{{Cough and cold preparations}}

{{Hallucinogens}}

{{Sigma receptor modulators}}

Category:Antitussives

Category:Methylenedioxyphenethylamines

Category:Natural opium alkaloids

Category:Pyrogallol ethers

Category:Sigma agonists

Category:3-(5,6,7,8-tetrahydro-(1,3)dioxolo(4,5-g)isoquinolin-5-yl)-3H-2-benzofuran-1-ones

Category:Hallucinogens

Category:Tetrahydroisoquinoline alkaloids