Chemistry:Higenamine

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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
UNII
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).
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Infobox references
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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).

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 United Kingdom , EU, the United States 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 5mg.[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). File:(S)-Norcoclaurine Biosynthesis.tif 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]

File:(S)-Norcoclaurine Biosynthesis- the final step.tif 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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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. 
  2. ↑ "Novel food catalogue". Food Safety. European Commission. http://ec.europa.eu/food/food/biotechnology/novelfood/novel_food_catalogue_en.htm. 
  3. ↑ "Prohibited Substances at All Times". World Anti-Doping Agency. 1 January 2016. http://list.wada-ama.org/prohibited-all-times/prohibited-substances/. 
  4. ↑ "Mamadou Sakho: Liverpool defender investigated over failed drugs test". BBC. 23 April 2016. https://www.bbc.co.uk/sport/football/36120459. 
  5. ↑ "Euro 2016: Mamadou Sakho could play for France as Uefa opts not to extend ban". BBC. 28 May 2016. https://www.bbc.co.uk/sport/football/36406071. 
  6. ↑ "Mamadou Sakho - UEFA decision raises key questions". Echo. 28 May 2016. http://www.liverpoolecho.co.uk/sport/football/football-news/mamadou-sakho-uefa-decision-raises-11399116. 
  7. ↑ "Mamadou Sakho still set to miss EURO 2016, despite being cleared of doping". Get French Football. 29 May 2016. http://www.getfootballnewsfrance.com/2016/mamadou-sakho-still-set-to-miss-euro-2016-despite-being-cleared-of-doping/. 
  8. ↑ 8.0 8.1 "Beta2-adrenoceptor-mediated tracheal relaxation induced by higenamine from Nandina domestica Thunberg". Planta Medica 75 (13): 1393–9. October 2009. doi:10.1055/s-0029-1185743. PMID 19468973. 
  9. ↑ "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. January 2005. doi:10.1016/j.bmc.2004.10.020. PMID 15598565. 
  10. ↑ "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. May 1989. doi:10.1254/jjp.50.75. PMID 2724702. 
  11. ↑ "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. October 1999. PMID 10490919. 
  12. ↑ "Anti-thrombotic effects of higenamine". Planta Medica 67 (7): 619–22. October 2001. doi:10.1055/s-2001-17361. PMID 11582538. 
  13. ↑ 13.0 13.1 "The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum". International Journal of Impotence Research 24 (2): 77–83. 2012. doi:10.1038/ijir.2011.48. PMID 21956762. 
  14. ↑ "Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist1". Acta Pharmacologica Sinica 29 (10): 1187–94. October 2008. doi:10.1111/j.1745-7254.2008.00859.x. PMID 18817623. 
  15. ↑ 15.0 15.1 "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. July 2008. doi:10.1016/j.bmcl.2008.05.094. PMID 18556200. 
  16. ↑ "Effects of higenamine on regulation of ion transport in guinea pig distal colon". Japanese Journal of Pharmacology 84 (3): 244–51. November 2000. doi:10.1254/jjp.84.244. PMID 11138724. 
  17. ↑ "Acute toxicity of higenamine in mice". Planta Medica 63 (1): 95–6. February 1997. doi:10.1055/s-2006-957619. PMID 9063102. 
  18. ↑ "Benzylisoquinoline alkaloid metabolism: a century of discovery and a brave new world". Plant & Cell Physiology 54 (5): 647–72. May 2013. doi:10.1093/pcp/pct020. PMID 23385146. 
  19. ↑ "The role of L-DOPA in plants". Plant Signaling & Behavior 9 (4): e28275. March 2014. doi:10.4161/psb.28275. PMID 24598311. 
  20. ↑ 20.0 20.1 "Benzylisoquinoline alkaloid biosynthesis in opium poppy". Planta 240 (1): 19–32. July 2014. doi:10.1007/s00425-014-2056-8. PMID 24671624. 
  21. ↑ "Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase" (in EN). Biochemistry 56 (40): 5274–5277. October 2017. doi:10.1021/acs.biochem.7b00769. PMID 28915025. 



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