Noscapine
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 family Papaveraceae (poppy family). It lacks significant hypnotic, euphoric, or analgesic effects affording it with very low addictive potential. This agent is primarily used for its antitussive (cough-suppressing) effects. Medical uses. Noscapine is often used as an antitussive medication. A 2012 Dutch guideline, however, does not recommend its use for acute coughing. Interactions. Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics. The drug  should not be taken with any MAOIs (monoamine oxidase inhibitors), as unknown and potentially fatal effects may occur. Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased. 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  Structure analysis. 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(3"H")-one). History. Noscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of "Narcotine" by Pierre  Robiquet, a French chemist in Paris. 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. Society and culture. 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. 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%. 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. 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. 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. Anticancer derivatives. Noscapine is itself an anti-mitiotic 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. Anti-Inflammatory Effects. Interestingly, 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 antiinflammatory effects . Moreover, they showed that the amount of inflammation reduction at this dose of noscapine is approximately equal to the indomethacin as a known and 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 IP-10/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 receptor (TLR), tumour necrosis factor α (TNF-α), and NO in human and mous macrophages without causing toxicity . Furthermore, brominated noscapine has potent anti-inflammatory activity in models of septic inflammation, inhibits inflammatory factors in a dose-dependent manner, and prevents the release of TNF-α and NO in human and mouse macrophages . Another study on inflammatory bowel disease (ulcerative colitis) and colon cancer found that noscapine had an excellent anti-inflammatory effect that could significantly decrease the levels of  proinflammatory factors such as IL-1β, IFN-c, and IL-6, compared to the control group . Additionally, it has been found that chitosan nanoparticles containing brominated noscapine derivatives could reduce proinflammatory cytokines such as IL-1β, IFN-c, and IL-6 and inflammation within colon mucosal tissue.