Noscapine

Last updated
Noscapine
Narkotin - Narcotine.svg
Noscapine.png
Clinical data
Other namesNarcotine
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • Contraindicated
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy medicine)
  • EU:BE, SE: otc (over-the-counter)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~30%
Elimination half-life 1.5 to 4 h (mean 2.5)
Identifiers
  • (3S)-6,7-Dimethoxy-3-[(5R)-5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo(4,5-g)isoquinolin-5-yl]-1(3H)-isobenzofuranone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.455 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H23NO7
Molar mass 413.421 g·mol−1
3D model (JSmol)
  • O=C2O[C@@H](c1ccc(OC)c(OC)c12)[C@@H]5N(C)CCc4c5c(OC)c3OCOc3c4
  • InChI=1S/C22H23NO7/c1-23-8-7-11-9-14-20(29-10-28-14)21(27-4)15(11)17(23)18-12-5-6-13(25-2)19(26-3)16(12)22(24)30-18/h5-6,9,17-18H,7-8,10H2,1-4H3/t17-,18+/m1/s1 Yes check.svgY
  • Key:AKNNEGZIBPJZJG-MSOLQXFVSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [1] This agent is primarily used for its antitussive (cough-suppressing) effects.

Contents

Medical uses

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

Side effects

Interactions

Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics. [4]

The drug should not be taken with any MAOIs (monoamine oxidase inhibitors), as unknown and potentially fatal effects may occur.[ citation needed ]

Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased. [5]

Biosynthesis

Noscapine Biosynthesis in P. somniferum Noscapine Biosynthesis.tif
Noscapine Biosynthesis in P. somniferum

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. [6]

The remainder of the noscapine biosynthetic pathway is largely governed by a single biosynthetic 10-gene cluster. [7] 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. [8] 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′. [9] 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. [10] Finally, an NAD +-dependent short-chain dehydrogenase (NOS) oxidizes the hemiacetal to a lactone, completing noscapine biosynthesis. [6]

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. [11] Noscapine, and its synthetic derivatives called noscapinoids, are known to interact with microtubules and inhibit cancer cell proliferation [12]

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(3H)-one).

History

Noscapine was first isolated and characterized in chemical breakdown and properties in 1803 under the denomination of "Narcotine" [13] [14] 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. [15] 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.

Society and culture

Recreational use

There are anecdotal reports of the recreational use of over-the-counter drugs in several countries, [16] 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. [17]

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%. [18]

Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine. [19] 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. [20] [21] 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. [22] [23]

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. [7] In 2016, the biosynthetic pathway of noscapine was reconstituted in yeast cells, [24] 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. [25] 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. [26]

Anticancer derivatives

Noscapine is itself an anti-mitiotic agent, therefore its analogs have great potential as novel anti-cancer drugs. [27] Analogs having significant cytotoxic effects through modified 1,3-benzodioxole moiety have been developed. [28] Similarly, N-alkyl amine, 1,3-diynyl, 9-vinyl-phenyl and 9-arylimino derivatives of noscapine have also been developed. [29] [30] [31] [32] Their mechanism of action is through tubulin inhibition. [33]

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. [34]

See also

Related Research Articles

<span class="mw-page-title-main">Morphine</span> Pain medication of the opiate family

Morphine is a strong opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies. It is mainly used as an analgesic. There are numerous methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; or via rectal suppository. It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are available as MS-Contin, Kadian, and other brand names as well as generically.

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Colchicine</span> Medication mainly used to treat gout

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<i>Papaver somniferum</i> Species of flowering plant in the family Papaveraceae

Papaver somniferum, commonly known as the opium poppy or breadseed poppy, is a species of flowering plant in the family Papaveraceae. It is the species of plant from which both opium and poppy seeds are derived and is also a valuable ornamental plant grown in gardens. Its native range was east of the Mediterranean Sea, but now is obscured by ancient introductions and cultivation, being naturalized across much of Europe and Asia.

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

Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasms and vasospasms, occasionally in the treatment of erectile dysfunction and acute mesenteric ischemia. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the analgesic morphine and its derivatives.

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

Scoulerine, also known as discretamine and aequaline, is a benzylisoquinoline alkaloid (BIA) that is derived directly from (S)-reticuline through the action of berberine bridge enzyme. It is a precursor of other BIAs, notably berberine, noscapine, (S)-tetrahydropalmatine, and (S)-stylopine, as well as the alkaloids protopine, and sanguinarine. It is found in many plants, including opium poppy, Croton flavens, and certain plants in the genus Erythrina.

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

Lycorine is a toxic crystalline alkaloid found in various Amaryllidaceae species, such as the cultivated bush lily, surprise lilies (Lycoris), and daffodils (Narcissus). It may be highly poisonous, or even lethal, when ingested in certain quantities. Regardless, it is sometimes used medicinally, a reason why some groups may harvest the very popular Clivia miniata.

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

Narcotoline is an opiate alkaloid chemically related to noscapine. It binds to the same receptors in the brain as noscapine to act as an antitussive, and has also been used in tissue culture media.

<span class="mw-page-title-main">Mitotic inhibitor</span> Cell division inhibitor

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

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The enzyme (S)-norcoclaurine synthase (EC 4.2.1.78) catalyzes the chemical reaction

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

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

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

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

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<span class="mw-page-title-main">Opiate</span> Substance derived from opium

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

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References

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