Noscapine, also known as narcotine, nectodon, nospen, anarcotine and (archaic) opiane, is a benzylisoquinoline

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the family

Papaveraceae The Papaveraceae, informally known as the poppy family, are an economically important family (biology), family of about 42 genera and approximately 775 known species of flowering plants in the order Ranunculales. The family is cosmopolitan dis ...

(poppy family). It lacks effects associated with

opioids Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

such as

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

, or

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

(pain-relief) and lacks addictive potential. Noscapine 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

cough A cough is a sudden expulsion of air through the large breathing passages which can help clear them of fluids, irritants, foreign particles and Microorganism, microbes. As a protective reflex, coughing can be repetitive with the cough reflex fol ...

ing.

Side effects

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

Vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

* Loss of coordination *

Hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

(auditory and visual) * Loss of sexual drive * Swelling of prostate * Loss of appetite * Dilated pupils * Increased heart rate * Shaking and

muscle spasms A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ, such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a musc ...

Chest pain Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...

* Increased

alertness Alertness is a state of active attention characterized by high sensory awareness. Someone who is alert is vigilant and promptly meets danger or emergency, or is quick to perceive and act. Alertness is a psychological and physiological state. Lac ...

* Increased

wakefulness Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognition, cognitive and behavioral responses to the external world. Being awake is the opposite of being asleep, ...

* Loss of

stereoscopic vision Binocular vision is seeing with two eyes, which increases the size of the visual field. If the visual fields of the two eyes overlap, binocular depth can be seen. This allows objects to be recognized more quickly, camouflage to be detected, spa ...

Interactions

Noscapine can increase the effects of centrally sedating substances such as

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

and

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

s. The drug should not be taken with

monoamine oxidase inhibitors Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...

(MAOIs), as unknown and potentially fatal effects may occur. Noscapine should not be taken in conjunction with

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

as the

anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...

effects of warfarin may be increased.

Biosynthesis

The biosynthesis of noscapine in '' P. somniferum'' begins with

chorismic acid Chorismic acid, more commonly known as its ion, anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for: * The aromatic amino acids phenylalanine, tryptophan, and tyrosine * Indole, ind ...

, which is synthesized via the shikimate pathway from erythrose 4-phosphate and

phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the carboxylic acid derived from the enol of pyruvate and a phosphate anion. It exists as an anion. PEP is an important intermediate in biochemistry. It has the high-energy phosphate, highest-e ...

. Chorismic acid is a precursor to the amino acid

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

, 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 Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. 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. 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 In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...

(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. 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 Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...

. Another

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

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′. 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. Finally, an NAD⁺-dependent short-chain dehydrogenase (NOS) oxidizes the hemiacetal to a lactone, completing noscapine biosynthesis.

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 An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Noscapine, and its synthetic derivatives called noscapinoids, are known to interact with microtubules and inhibit cancer cell proliferation

Structure analysis

The

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

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 Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid (English in the Commonwealth of Nations, Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen, ...

and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro- ,3ioxolo ,5-''g''soquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

/ 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 1803 under the denomination of "Narcotine" 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. 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 Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

, and also isolated in 1832 another very important component of raw opium, that he called

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

, currently a widely used opium-derived compound.

Society and culture

Recreational use

There are anecdotal reports of the recreational use of

over-the-counter drug Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...

s 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 Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

and

alcohol intoxication Alcohol intoxication, commonly described in higher doses as drunkenness or inebriation, and known in overdose as alcohol poisoning, is the behavior and physical effects caused by recent consumption of Alcohol (drug), alcohol. The technical ter ...

. Unlike dextromethorphan, noscapine is not an

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

Noscapine in heroin

Noscapine can survive the manufacturing processes of

heroin Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...

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 Liège ( ; ; ; ; ) is a City status in Belgium, city and Municipalities in Belgium, municipality of Wallonia, and the capital of the Liège Province, province of Liège, Belgium. The city is situated in the valley of the Meuse, in the east o ...

Belgium Belgium, officially the Kingdom of Belgium, is a country in Northwestern Europe. Situated in a coastal lowland region known as the Low Countries, it is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeas ...

, 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 Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...

. 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 Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

samples alongside noscapine include

papaverine Papaverine (Latin '' papaver'', "poppy") is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasms and vasospasms (especially those involving the intestines, heart, or brain), occasionally in the treatment of ...

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 Polyploidy is a condition in which the cells of an organism have more than two paired sets of ( homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two complete sets of chromosomes, one fro ...

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 Polyploidy is a condition in which the cells of an organism have more than two paired sets of ( homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two complete sets of chromosomes, one fro ...

induction by noscapine is suggested to involve either chromosome

spindle apparatus In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter Cell (biology), cells. It is referred to as the mitotic spindle during mitos ...

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 antimitotic agent, therefore its analogs have great potential as novel anti-cancer drugs. Analogs having significant

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

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

Various studies have indicated that noscapine has

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...

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 Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

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 Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of pr ...

, a standard anti-inflammatory medication. Furthermore, Shiri et al. concluded that noscapine prevented the progression of

bradykinin Bradykinin (BK) (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpo ...

-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 Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

TNF-α and the

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...

CXCL10 from

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

, 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 Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...

(TLR), TNF-α, and

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...

(NO) in human and mouse macrophages without causing toxicity.

References

{{Sigma receptor modulators Antitussives Methylenedioxyphenethylamines Natural opium alkaloids Pyrogallol ethers Sigma agonists 3-(5,6,7,8-tetrahydro-(1,3)dioxolo(4,5-g)isoquinolin-5-yl)-3H-2-benzofuran-1-ones Hallucinogens Tetrahydroisoquinoline alkaloids