 | |
 | |
| Clinical data | |
|---|---|
| Other names | Narcotine, nectodon, nospen, anarcotine |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy category |
|
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | ~30% |
| Eliminationhalf-life | 1.5–4 h (mean 2.5 h) |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.004.455 |
| Chemical and physical data | |
| Formula | C22H23NO7 |
| Molar mass | 413.426 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
 N Y (what is this?) (verify) | |
Noscapine, also known asnarcotine,nectodon,nospen,anarcotine and (archaic)opiane, is abenzylisoquinolinealkaloid of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the familyPapaveraceae (poppy family). It lacks effects associated withopioids such assedation,euphoria, oranalgesia (pain-relief) and lacks addictive potential.[1] Noscapine is primarily used for itsantitussive (cough-suppressing) effects.
Noscapine is often used as anantitussive medication.[2] A 2012 Dutch guideline, however, does not recommend its use foracutecoughing.[3]
Noscapine can increase the effects of centrally sedating substances such asalcohol andhypnotics.[4]
The drug should not be taken withmonoamine oxidase inhibitors (MAOIs), as unknown and potentially fatal effects may occur.[citation needed]
Noscapine should not be taken in conjunction withwarfarin as theanticoagulant effects of warfarin may be increased.[5]
The biosynthesis of noscapine inP. somniferum begins withchorismic acid, which is synthesized via theshikimate pathway fromerythrose 4-phosphate andphosphoenolpyruvate. Chorismic acid is a precursor to the amino acidtyrosine, the source of nitrogen inbenzylisoquinoline alkaloids. Tyrosine can undergo aPLP-mediated transamination to form4-hydroxyphenylpyruvic acid (4-HPP), followed by aTPP-mediated decarboxylation to form4-hydroxyphenylacetaldehyde (4-HPAA). Tyrosine can also be hydroxylated to form3,4-dihydroxyphenylalanine (DOPA), followed by a PLP-mediated decarboxylation to formdopamine.Norcoclaurine synthase (NCS) catalyzes aPictet-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 cofactorsS-adenosyl-methionine (SAM) andNADP+ 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 cofactorflavin adenine dinucleotide (FAD). Next, anO-methyltransferase (SOMT) methylates the 9-hydroxyl group. Canadine synthase (CAS) catalyzes the formation of a unique C2-C3 methylenedioxy bridge in (S)-canadine.[8] AnN-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) usingacetyl-CoA. Anothercytochrome 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-mediatedO-methylation on C4′.[9] TheO-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, anNAD+-dependentshort-chain dehydrogenase (NOS) oxidizes the hemiacetal to a lactone, completing noscapine biosynthesis.[6]
Noscapine's antitussive effects appear to be primarily mediated by itsσ–receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment withrimcazole, a σ-specificantagonist, 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]
Thelactone 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 ofsulfuric acid and heating it dissociates intocotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline) andopic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced withzinc/HCl, the bond C1−C3′ saturates and the molecule dissociates intohydrocotarnine (2-hydroxycotarnine) andmeconine (6,7-dimethoxyisobenzofuran-1(3H)-one).
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. ThenPierre-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 ofmorphine, and also isolated in 1832 another very important component of raw opium, that he calledcodeine, currently a widely used opium-derivedcompound.
There are anecdotal reports of the recreational use ofover-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 todextromethorphan andalcohol intoxication. Unlike dextromethorphan, noscapine is not anNMDA receptor antagonist.[17]
Noscapine can survive the manufacturing processes ofheroin 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 inLiège,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 prescribeddiamorphine.[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 inurine samples alongside noscapine includepapaverine andacetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites,cotarnine andmeconine. Detection is performed bygas 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 certainhematological malignancies has been explored in the clinic.[20][21]Polyploidy induction by noscapine has been observedin 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 ofpolyploidy induction by noscapine is suggested to involve either chromosomespindle apparatus damage or cell fusion.[22][23]
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 yieldin plantae to be mass-produced, allowing them to become marketable therapeutic drugs.[26]
Noscapine is itself anantimitotic agent, therefore its analogs have great potential as novel anti-cancer drugs.[27] Analogs having significantcytotoxic effects through modified1,3-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 throughtubulin inhibition.[33]
Various studies have indicated that noscapine hasanti-inflammatory effects and significantly reduces the levels of proinflammatory factors such asinterleukin 1β (IL-1β), IFN-c, and IL-6. In this regard, in another study, Khakpour et al. examined the effect of noscapine against carrageenan-inducedinflammation 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 toindomethacin, a standard anti-inflammatory medication. Furthermore, Shiri et al. concluded that noscapine prevented the progression ofbradykinin-induced inflammation in the rat's foot by antagonisingbradykinin receptors. In addition, Zughaier et al. evaluated the anti-inflammatory effects ofbrominated noscapine. The brominated form of noscapine has been shown to inhibit the secretion of thecytokineTNF-α and thechemokineCXCL10 frommacrophages, 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 inhibitstoll-like receptors (TLR), TNF-α, andnitric oxide (NO) in human and mouse macrophages without causing toxicity.