Higenamine

Last updated
Higenamine
Higenamine.svg
Names
IUPAC name
1-[(4-Hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol
Other names
norcoclaurine, demethylcoclaurine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
MeSH higenamine
PubChem CID
UNII
  • InChI=1S/C16H17NO3/c18-12-3-1-10(2-4-12)7-14-13-9-16(20)15(19)8-11(13)5-6-17-14/h1-4,8-9,14,17-20H,5-7H2 Yes check.svgY
    Key: WZRCQWQRFZITDX-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C16H17NO3/c18-12-3-1-10(2-4-12)7-14-13-9-16(20)15(19)8-11(13)5-6-17-14/h1-4,8-9,14,17-20H,5-7H2
    Key: WZRCQWQRFZITDX-UHFFFAOYAH
  • Oc1ccc(cc1)CC3c2c(cc(O)c(O)c2)CCN3
Properties
C16H17NO3
Molar mass 271.316 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Higenamine (norcoclaurine) is a chemical compound found in a variety of plants including Nandina domestica (fruit), Aconitum carmichaelii (root), Asarum heterotropioides , Galium divaricatum (stem and vine), Annona squamosa , and Nelumbo nucifera (lotus seeds).

Contents

Higenamine is found as an ingredient in sports and weight loss dietary supplements sold in the US. [1] The US Food and Drug Administration has received reports of adverse effects from higenamine-containing supplements since 2014, but higenamine's health risks remain poorly understood. [1]

Legality

Higenamine, also known as norcoclaurine HCl, is legal to use within food supplements in the UK, EU, the USA and Canada. Its main use is within food supplements developed for weight management and sports supplements. [1] Traditional formulations with higenamine have been used for thousands of years within Chinese medicine and come from a variety of sources including fruit and orchids. There are no studies comparing the safety of modern formulations (based on synthetic higenamine) with traditional formulations. Nevertheless, it will not be added to the EU 'novel foods' catalogue, which details all food supplements that require a safety assessment certificate before use. [2]

Along with many other β2 agonists, higenamine is prohibited by World Anti-Doping Agency for use in sports. [3] In 2016, French footballer Mamadou Sakho was temporarily banned by UEFA after testing positive for Higenamine causing the player to miss the 2016 Europa League final. The ban was lifted after the player successfully made the mitigating defence that there was an absence of significant negligence as the substance was not on the list of banned substances despite drugs of the same category – β2 agonists – being banned. [4] [5] [6] [7]

Pharmacology

Since higenamine is present in plants which have a history of use in traditional medicine, the pharmacology of this compound has attracted scientific interest.

In animal models, higenamine has been demonstrated to be a β2 adrenoreceptor agonist. [8] [9] [10] [11] [12] Adrenergic receptors, or adrenoceptors, belong to the class of G protein–coupled receptors, and are the most prominent receptors in the adipose membrane, besides also being expressed in skeletal muscle tissue. These adipose membrane receptors are classified as either α or β adrenoceptors. Although these adrenoceptors share the same messenger, cyclic adenosine monophosphate (cAMP), the specific transduction pathway depends on the receptor type (α or β). Higenamine partly exerts its actions by the activation of an enzyme, adenylate cyclase, responsible for boosting the cellular concentrations of the adrenergic second messenger, cAMP. [13]

In a rodent model, it was found that higenamine produced cardiotonic, vascular relaxation, and bronchodilator effects. [14] [15] In particular, higenamine, via a beta-adrenoceptor mechanism, induced relaxation in rat corpus cavernosum, leading to improved vasodilation and erectile function.

Related to improved vasodilatory signals, higenamine has been shown in animal models to possess antiplatelet and antithrombotic activity via a cAMP-dependent pathway, suggesting higenamine may contribute to enhanced vasodilation and arterial integrity. [8] [13] [15] [16]

In humans, higenamine has been studied as an investigational drug in China for use as a pharmacological agent for cardiac stress tests as well as for treatment of a number of cardiac conditions including bradyarrhythmias. [1] The human trials were relatively small (ranging from 10 to 120 subjects) and higenamine was administered intravenously, most commonly using gradual infusions of 2.5 or 5 mg. [1] Higenamine consistently increased heart rate but had variable effects on blood pressure. One small study described higenamine's effect on cardiac output: higenamine led to an increased ejection fraction in 15 patients with heart disease. [1]

Toxicity

The safety of orally administered higenamine in humans is unknown. During a study of acute toxicity, mice were orally administered the compound at a dose of 2 g per kg of bodyweight. No mice died during the study. [17] In human trials of intravenous higenamine, subjects who received higenamine reported shortness of breath, racing heart, dizziness, headaches, chest tightness. [1]

Biosynthesis

(S)-Norcoclaurine/Higenamine is at the center of benzylisoquinoline alkaloid (BIA) biosynthesis. In spite of large structure diversity, BIAs biosynthesis all share a common first committed intermediate (S)-norcoclaurine. [18] (S)-norcoclaurine is produced by the condensation of two tyrosine derivatives, dopamine and 4-hydroxyphenylacetaldehyde (4-HPAA).

Synthesis of the two substrates: dopamine and 4-HPAA (S)-Norcoclaurine Biosynthesis.tif
Synthesis of the two substrates: dopamine and 4-HPAA

In plants, tyrosine is synthesized through Shikimate pathway, during which the last step involves decarboxylation and dehydrogenation of arogenate to give L-tyrosine. To generate dopamine from tyrosine, there are two pathways. In one pathway, tyrosine undergoes decarboxylation catalyzed by tyrosine decarboxylase (TyrDC) to become tyramine, which is then followed by oxidation of polyphenol oxidase (PPO) to render dopamine. [19] [20] Alternatively, tyrosine can be oxidized by tyrosine hydroxylase (TH) to form L-DOPA, which is then later decarboxylated by DOPA decarboxylase (DDC) to provide dopamine. Besides that, the other starting material, 4-HPAA, is generated through a first transamination by tyrosine transeaminase (TyrAT) to form 4-hydroxylphenylpyruvate (4-HPP), and a subsequent decarboxylation by 4-HPP decarboxylase. [20]

Synthesis of (S)-Higenamine by NCS and its mechanism. (S)-Norcoclaurine Biosynthesis- the final step.tif
Synthesis of (S)-Higenamine by NCS and its mechanism.

The condensation of dopamine and 4-HPAA to form (S)-norcoclaurine is catalyzed by (S)-norcoclaurine synthase (NCS). [21] Such reaction is one type of Pictet-Spengler reaction. In this reaction, Asp-141 and Glu-110 in the NCS active site are involved in the activation of the amine and carbonyl respectively to facilitate imine formation. Then, the molecule will be cyclized as the mechanism shown below to produce (S)-nococlaurine.

See also

Related Research Articles

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Adrenergic receptor</span> Class of G protein-coupled receptors

The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.

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

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. In some plant families, l-DOPA is the central precursor of a biosynthetic pathway that produces a class of pigments called betalains. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

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

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

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

Noscapine is a benzylisoquinoline alkaloid, of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the family Papaveraceae. 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.

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

Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<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">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

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

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

Pukateine is an alkaloid found in the bark of the New Zealand tree Laurelia novae-zelandiae ("Pukatea"), as well as some South American plants. An extract from pukatea is used in traditional Māori herbal medicine as an analgesic.

<span class="mw-page-title-main">Aromatic L-amino acid decarboxylase inhibitor</span>

An aromatic L-amino acid decarboxylase inhibitor is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase. It is used to inhibit the decarboxylation of L-DOPA to dopamine outside the brain, i.e. in the blood. This is primarily co-administered with L-DOPA to combat Parkinson's disease. Administration can prevent common side-effects, such as nausea and vomiting, as a result of interaction with D2 receptors in the vomiting center located outside the blood–brain barrier.

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

Substitution of the heterocycle isoquinoline at the C1 position by a benzyl group provides 1‑benzylisoquinoline, the most widely examined of the numerous benzylisoquinoline structural isomers. The 1-benzylisoquinoline moiety can be identified within numerous compounds of pharmaceutical interest, such as moxaverine; but most notably it is found within the structures of a wide variety of plant natural products, collectively referred to as benzylisoquinoline alkaloids. This class is exemplified in part by the following compounds: papaverine, noscapine, codeine, morphine, apomorphine, berberine, tubocurarine.

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

Ajmalicine, also known as δ-yohimbine or raubasine, is an antihypertensive drug used in the treatment of high blood pressure. It has been marketed under numerous brand names including Card-Lamuran, Circolene, Cristanyl, Duxil, Duxor, Hydroxysarpon, Iskedyl, Isosarpan, Isquebral, Lamuran, Melanex, Raunatin, Saltucin Co, Salvalion, and Sarpan. It is an alkaloid found naturally in various plants such as Rauvolfia spp., Catharanthus roseus, and Mitragyna speciosa.

<span class="mw-page-title-main">History of catecholamine research</span>

The catecholamines are a group of neurotransmitters composed of the endogenous substances dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine), as well as numerous artificially synthesized compounds such as isoprenaline - an anti-bradycardiac medication. Their investigation constitutes a major chapter in the history of physiology, biochemistry, and pharmacology. Adrenaline was the first hormone extracted from an endocrine gland and obtained in pure form, before the word hormone was coined. Adrenaline was also the first hormone whose structure and biosynthesis was discovered. Second to acetylcholine, adrenaline and noradrenaline were some of the first neurotransmitters discovered, and the first intercellular biochemical signals to be found in intracellular vesicles. The β-adrenoceptor gene was the first G protein-coupled receptor to be cloned.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

<span class="mw-page-title-main">4-Hydroxyphenylacetaldehyde</span> Chemical compound

4-Hydroxyphenylacetaldehyde, also known as p-hydroxyphenylacetaldehyde, is a natural product with the formula HOC6H4CH2CHO. It is a derivative of phenylacetaldehyde and occurs as a white solid at room temperature.

References

  1. 1 2 3 4 5 6 7 Cohen, Pieter A.; Travis, John C.; Keizers, Peter H. J.; Boyer, Frederick E.; Venhuis, Bastiaan J. (6 September 2018). "The stimulant higenamine in weight loss and sports supplements". Clinical Toxicology. 57 (2): 125–130. doi:10.1080/15563650.2018.1497171. PMID   30188222. S2CID   52165506.
  2. ↑ "Novel food catalogue". Food Safety. European Commission.
  3. ↑ "Prohibited Substances at All Times". List of Prohibited Substances and Methods. World Anti-Doping Agency. 1 January 2016. Archived from the original on 20 August 2016. Retrieved 21 August 2016.
  4. ↑ "Mamadou Sakho: Liverpool defender investigated over failed drugs test". BBC. 23 April 2016.
  5. ↑ "Euro 2016: Mamadou Sakho could play for France as Uefa opts not to extend ban". BBC. 28 May 2016.
  6. ↑ "Mamadou Sakho - UEFA decision raises key questions". Echo. 28 May 2016.
  7. ↑ "Mamadou Sakho still set to miss EURO 2016, despite being cleared of doping". Get French Football. 29 May 2016.
  8. 1 2 Tsukiyama M, Ueki T, Yasuda Y, Kikuchi H, Akaishi T, Okumura H, Abe K (October 2009). "Beta2-adrenoceptor-mediated tracheal relaxation induced by higenamine from Nandina domestica Thunberg". Planta Medica. 75 (13): 1393–9. doi:10.1055/s-0029-1185743. PMID   19468973. S2CID   260280804.
  9. ↑ Kashiwada Y, Aoshima A, Ikeshiro Y, Chen YP, Furukawa H, Itoigawa M, Fujioka T, Mihashi K, Cosentino LM, Morris-Natschke SL, Lee KH (January 2005). "Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids". Bioorganic & Medicinal Chemistry. 13 (2): 443–8. doi:10.1016/j.bmc.2004.10.020. PMID   15598565.
  10. ↑ Kimura I, Chui LH, Fujitani K, Kikuchi T, Kimura M (May 1989). "Inotropic effects of (+/-)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional sino-Japanese medicines "bushi" and "shin-i" in isolated guinea pig papillary muscle". Japanese Journal of Pharmacology. 50 (1): 75–8. doi: 10.1254/jjp.50.75 . PMID   2724702.
  11. ↑ Kang YJ, Lee YS, Lee GW, Lee DH, Ryu JC, Yun-Choi HS, Chang KC (October 1999). "Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root". The Journal of Pharmacology and Experimental Therapeutics. 291 (1): 314–20. PMID   10490919.
  12. ↑ Yun-Choi HS, Pyo MK, Park KM, Chang KC, Lee DH (October 2001). "Anti-thrombotic effects of higenamine". Planta Medica. 67 (7): 619–22. doi:10.1055/s-2001-17361. PMID   11582538. S2CID   260279615.
  13. 1 2 Kam SC, Do JM, Choi JH, Jeon BT, Roh GS, Chang KC, Hyun JS (2012). "The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum". International Journal of Impotence Research. 24 (2): 77–83. doi: 10.1038/ijir.2011.48 . PMID   21956762.
  14. ↑ Bai G, Yang Y, Shi Q, Liu Z, Zhang Q, Zhu YY (October 2008). "Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist1". Acta Pharmacologica Sinica. 29 (10): 1187–94. doi: 10.1111/j.1745-7254.2008.00859.x . PMID   18817623.
  15. 1 2 Pyo MK, Lee DH, Kim DH, Lee JH, Moon JC, Chang KC, Yun-Choi HS (July 2008). "Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation". Bioorganic & Medicinal Chemistry Letters. 18 (14): 4110–4. doi:10.1016/j.bmcl.2008.05.094. PMID   18556200.
  16. ↑ Liu W, Sato Y, Hosoda Y, Hirasawa K, Hanai H (November 2000). "Effects of higenamine on regulation of ion transport in guinea pig distal colon". Japanese Journal of Pharmacology. 84 (3): 244–51. doi: 10.1254/jjp.84.244 . PMID   11138724.
  17. ↑ Lo CF, Chen CM (February 1997). "Acute toxicity of higenamine in mice". Planta Medica. 63 (1): 95–6. doi:10.1055/s-2006-957619. PMID   9063102. S2CID   260281301.
  18. ↑ Hagel JM, Facchini PJ (May 2013). "Benzylisoquinoline alkaloid metabolism: a century of discovery and a brave new world". Plant & Cell Physiology. 54 (5): 647–72. doi: 10.1093/pcp/pct020 . PMID   23385146.
  19. ↑ Soares AR, Marchiosi R, Siqueira-Soares RC, Barbosa de Lima R, Marchiosi R, Dantas dos Santos W, Ferrarese-Filho O (March 2014). "The role of L-DOPA in plants". Plant Signaling & Behavior. 9 (4): e28275. Bibcode:2014PlSiB...9E8275S. doi:10.4161/psb.28275. PMC   4091518 . PMID   24598311.
  20. 1 2 Beaudoin GA, Facchini PJ (July 2014). "Benzylisoquinoline alkaloid biosynthesis in opium poppy". Planta. 240 (1): 19–32. Bibcode:2014Plant.240...19B. doi: 10.1007/s00425-014-2056-8 . PMID   24671624.
  21. ↑ Lichman BR, Sula A, Pesnot T, Hailes HC, Ward JM, Keep NH (October 2017). "Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase". Biochemistry. 56 (40): 5274–5277. doi:10.1021/acs.biochem.7b00769. PMC   5637010 . PMID   28915025.
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