Higenamine: Difference between revisions

{{more medical citations needed|date=December 2018}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid =

|ImageFile= Higenamine.

|ImageSize=200px

|IUPACName=1-[(4-)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol

| OtherNames = norcoclaurine, demethylcoclaurine

|Section1={{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| CASNo_Ref = {{cascite|correct|}}

| CASNo1=106032-53-5

| CASNo1_Ref = {{cascite|correct|}}

| CASNo1_Comment = (''R'')

| CASNo2=22672-77-1

| CASNo2_Ref = {{cascite|correct|}}

| CASNo2_Comment = (''S'')

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = TBV5O16GAP

| UNII1_Ref = {{fdacite|correct|FDA}}

| UNII1 = 6016M93W29

| UNII1_Comment = (''R'')

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = P94O9O6QM5

| UNII2_Comment = (''S'')

| PubChem=114840

| ChEBI = 18418

| ChEBI_Ref = {{ebicite|correct|EBI}}

| MeSHName=higenamine

|Section2={{Chembox Properties

| C=16 | H=17 | N=1 | O=3

| Appearance=

| Density=

| MeltingPt=

| BoilingPt=

| Solubility=

|Section3={{Chembox Hazards

| =

| FlashPt=

| AutoignitionPt =

'''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.<ref name="Clin Tox"/> 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.<ref name="Clin Tox"/>

==Legality==

Higenamine, also known as norcoclaurine [[Hydrochloride|HCl]], is legal to use within food supplements in the [[United Kingdom|UK]], [[European Union|EU]], the [[United States|USA]] and [[Canada]]. Its main use is within food supplements developed for weight management and sports supplements.<ref name="Clin Tox"/> 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.<ref>{{cite web | title = Novel food catalogue | url = http://ec.europa.eu/food/food/biotechnology/novelfood/novel_food_catalogue_en.htm | work = Food Safety | publisher = European Commission }}</ref>

Along with many other [[Beta2-adrenergic agonist|β₂ agonists]], higenamine is prohibited by [[World Anti-Doping Agency]] for use in sports.<ref>{{cite web|title=Prohibited Substances at All Times|url=http://list.wada-ama.org/prohibited-all-times/prohibited-substances/|website=List of Prohibited Substances and Methods|publisher=World Anti-Doping Agency|access-date=21 August 2016|date=1 January 2016}}</ref> 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.<ref>{{cite web | title = Mamadou Sakho: Liverpool defender investigated over failed drugs test | url = https://www.bbc.co.uk/sport/football/36120459 | work = BBC | date = 23 April 2016 }}</ref><ref>{{cite web | title = Euro 2016: Mamadou Sakho could play for France as Uefa opts not to extend ban | url = https://www.bbc.co.uk/sport/football/36406071 | work = BBC | date = 28 May 2016 }}</ref><ref>{{cite web | title = Mamadou Sakho - UEFA decision raises key questions | url = http://www.liverpoolecho.co.uk/sport/football/football-news/mamadou-sakho-uefa-decision-raises-11399116 | work = Echo | date = 28 May 2016 }}</ref><ref>{{cite web | title = Mamadou Sakho still set to miss EURO 2016, despite being cleared of doping | url = http://www.getfootballnewsfrance.com/2016/mamadou-sakho-still-set-to-miss-euro-2016-despite-being-cleared-of-doping/ | work = Get French Football | date = 29 May 2016 }}</ref>

==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 [[Beta2-adrenergic agonist|β₂ adrenoreceptor agonist]].<ref name=Tsukiyama >{{cite journal | vauthors = Tsukiyama M, Ueki T, Yasuda Y, Kikuchi H, Akaishi T, Okumura H, Abe K | title = Beta2-adrenoceptor-mediated tracheal relaxation induced by higenamine from Nandina domestica Thunberg | journal = Planta Medica | volume = 75 | issue = 13 | pages = 1393–9 | date = October 2009 | pmid = 19468973 | doi = 10.1055/s-0029-1185743 | s2cid = 260280804 }}</ref><ref name=Kashiwada>{{cite journal | vauthors = Kashiwada Y, Aoshima A, Ikeshiro Y, Chen YP, Furukawa H, Itoigawa M, Fujioka T, Mihashi K, Cosentino LM, Morris-Natschke SL, Lee KH | title = Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids | journal = Bioorganic & Medicinal Chemistry | volume = 13 | issue = 2 | pages = 443–8 | date = January 2005 | pmid = 15598565 | doi = 10.1016/j.bmc.2004.10.020 }}</ref><ref name=Kimura>{{cite journal | vauthors = Kimura I, Chui LH, Fujitani K, Kikuchi T, Kimura M | title = 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 | journal = Japanese Journal of Pharmacology | volume = 50 | issue = 1 | pages = 75–8 | date = May 1989 | pmid = 2724702 | doi = 10.1254/jjp.50.75 | doi-access = free }}</ref><ref name=Kang>{{cite journal | vauthors = Kang YJ, Lee YS, Lee GW, Lee DH, Ryu JC, Yun-Choi HS, Chang KC | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 291 | issue = 1 | pages = 314–20 | date = October 1999 | pmid = 10490919 }}</ref><ref name=Yun>{{cite journal | vauthors = Yun-Choi HS, Pyo MK, Park KM, Chang KC, Lee DH | title = Anti-thrombotic effects of higenamine | journal = Planta Medica | volume = 67 | issue = 7 | pages = 619–22 | date = October 2001 | pmid = 11582538 | doi = 10.1055/s-2001-17361 | s2cid = 260279615 }}</ref> Adrenergic receptors, or adrenoceptors, belong to the class of [[G protein–coupled receptor]]s, and are the most prominent receptors in the [[Adipose tissue|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, [[Adenylyl cyclase|adenylate cyclase]], responsible for boosting the cellular concentrations of the adrenergic second messenger, cAMP.<ref name=Kam>{{cite journal | vauthors = Kam SC, Do JM, Choi JH, Jeon BT, Roh GS, Chang KC, Hyun JS | title = The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum | journal = International Journal of Impotence Research | volume = 24 | issue = 2 | pages = 77–83 | year = 2012 | pmid = 21956762 | doi = 10.1038/ijir.2011.48 | doi-access = free }}</ref>

In a rodent model, it was found that higenamine produced [[Cardiac stimulant|cardiotonic]], vascular relaxation, and [[bronchodilator]] effects.<ref name=Bai>{{cite journal | vauthors = Bai G, Yang Y, Shi Q, Liu Z, Zhang Q, Zhu YY | title = Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist1 | journal = Acta Pharmacologica Sinica | volume = 29 | issue = 10 | pages = 1187–94 | date = October 2008 | pmid = 18817623 | doi = 10.1111/j.1745-7254.2008.00859.x | doi-access = free }}</ref><ref name=Pyo>{{cite journal | vauthors = Pyo MK, Lee DH, Kim DH, Lee JH, Moon JC, Chang KC, Yun-Choi HS | title = Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 14 | pages = 4110–4 | date = July 2008 | pmid = 18556200 | doi = 10.1016/j.bmcl.2008.05.094 }}</ref> In particular, higenamine, via a beta-adrenoceptor mechanism, induced relaxation in rat [[Corpus cavernosum penis|corpus cavernosum]], leading to improved [[vasodilation]] and erectile function.

Related to improved vasodilatory signals, higenamine has been shown in animal models to possess [[Antiplatelet drug|antiplatelet]] and [[antithrombotic]] activity via a cAMP-dependent pathway, suggesting higenamine may contribute to enhanced vasodilation and arterial integrity.<ref name=Tsukiyama/><ref name="Kam"/><ref name=Pyo/><ref name=Liu>{{cite journal | vauthors = Liu W, Sato Y, Hosoda Y, Hirasawa K, Hanai H | title = Effects of higenamine on regulation of ion transport in guinea pig distal colon | journal = Japanese Journal of Pharmacology | volume = 84 | issue = 3 | pages = 244–51 | date = November 2000 | pmid = 11138724 | doi = 10.1254/jjp.84.244 | doi-access = free }}</ref>

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.<ref name = "Clin Tox">{{cite journal |last1=Cohen |first1=Pieter A. |last2=Travis |first2=John C. |last3=Keizers |first3=Peter H. J. |last4=Boyer |first4=Frederick E. |last5=Venhuis |first5=Bastiaan J. |title=The stimulant higenamine in weight loss and sports supplements |journal=Clinical Toxicology |volume=57 |issue=2 |date=6 September 2018 |pages=125–130 |doi=10.1080/15563650.2018.1497171|pmid=30188222 |s2cid=52165506 }}</ref> 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&nbsp;mg.<ref name="Clin Tox"/> 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.<ref name="Clin Tox"/>

==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.<ref name=Lo>{{cite journal | vauthors = Lo CF, Chen CM | title = Acute toxicity of higenamine in mice | journal = Planta Medica | volume = 63 | issue = 1 | pages = 95–6 | date = February 1997 | pmid = 9063102 | doi = 10.1055/s-2006-957619 | s2cid = 260281301 }}</ref> In human trials of intravenous higenamine, subjects who received higenamine reported shortness of breath, racing heart, dizziness, headaches, chest tightness.<ref name="Clin Tox"/>

== Biosynthesis ==

(S)-Norcoclaurine/Higenamine is at the center of [[Benzylisoquinoline alkaloids|benzylisoquinoline alkaloid]] (BIA) biosynthesis. In spite of large structure diversity, BIAs biosynthesis all share a common first committed intermediate (S)-norcoclaurine.<ref>{{cite journal | vauthors = Hagel JM, Facchini PJ | title = Benzylisoquinoline alkaloid metabolism: a century of discovery and a brave new world | journal = Plant & Cell Physiology | volume = 54 | issue = 5 | pages = 647–72 | date = May 2013 | pmid = 23385146 | doi = 10.1093/pcp/pct020 | doi-access = free }}</ref> (S)-norcoclaurine is produced by the condensation of two tyrosine derivatives, dopamine and 4-hydroxyphenylacetaldehyde (4-HPAA).

[[File:(S)-Norcoclaurine Biosynthesis.tif|alt=Synthesis of the two substrates: dopamine and 4-HPAA|thumb|496x496px|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 [[Tyrosine|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.<ref>{{cite journal | vauthors = Soares AR, Marchiosi R, Siqueira-Soares RC, Barbosa de Lima R, Marchiosi R, Dantas dos Santos W, Ferrarese-Filho O |title=The role of L-DOPA in plants |journal=Plant Signaling & Behavior |date=March 2014 |volume=9 |issue=4 |pages=e28275 |doi=10.4161/psb.28275|pmid=24598311 |pmc=4091518 }}</ref><ref name="Beaudoin_2014">{{cite journal | vauthors = Beaudoin GA, Facchini PJ | title = Benzylisoquinoline alkaloid biosynthesis in opium poppy | journal = Planta | volume = 240 | issue = 1 | pages = 19–32 | date = July 2014 | pmid = 24671624 | doi = 10.1007/s00425-014-2056-8 | doi-access = free }}</ref> 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.<ref name="Beaudoin_2014" />

[[File:(S)-Norcoclaurine Biosynthesis- the final step.tif|alt=Synthesis of (S)-Higenamine by NCS and its mechanism.|thumb|498x498px|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).<ref>{{cite journal | vauthors = Lichman BR, Sula A, Pesnot T, Hailes HC, Ward JM, Keep NH | title = Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase | language = EN | journal = Biochemistry | volume = 56 | issue = 40 | pages = 5274–5277 | date = October 2017 | pmid = 28915025 | pmc = 5637010 | doi = 10.1021/acs.biochem.7b00769 }}</ref> Such reaction is one type of [[Pictet–Spengler reaction|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 ==

* [[Papaverine]]

==References==

{{Reflist|2}}

[[Category:Benzylisoquinoline alkaloids]]

[[Category:]]