Chemistry:Harmine

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Harmine
Harmine structure.svg
Harmine 3d structure.png
Names
Preferred IUPAC name
7-Methoxy-1-methyl-9H-pyrido[3,4-b]indole
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
KEGG
UNII
Properties
C13H12N2O
Molar mass 212.25 g/mol
Density 1.326 g/cm3
Melting point 321 °C (610 °F; 594 K) (·HCl); 262 °C (·HCl·2H2O)[2]
insoluble[1]
Solubility in Dimethyl sulfoxide 100mM[1]
Solubility in Ethanol 1 mg/mL[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

Harmine is a beta-carboline and a harmala alkaloid. It occurs in a number of different plants, most notably the Syrian rue and Banisteriopsis caapi.[3] Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamines, making it a Reversible inhibitor of monoamine oxidase A (RIMA). Harmine does not inhibit MAO-B.[4] Harmine is also known as banisterin, banisterine, telopathin, telepathine, leucoharmine[5] and yagin, yageine.[3][6]

Biosynthesis

The coincident occurrence of β-carboline alkaloids and serotonin in Peganum harmala indicates the presence of two very similar, interrelated biosynthetic pathways, which makes it difficult to definitively identify whether free tryptamine or L-tryptophan is the precursor in the biosynthesis of harmine.[7] However, it is postulated that L-tryptophan is the most likely precursor, with tryptamine existing as an intermediate in the pathway.

The following figure shows the proposed biosynthetic scheme for harmine.[8] The Shikimate acid pathway yields the aromatic amino acid, L-tryptophan. Decarboxylation of L-tryptophan by aromatic L-amino acid decarboxylase (AADC) produces tryptamine (I), which contains a nucleophilic center at the C-2 carbon of the indole ring due to the adjacent nitrogen atom that enables the participation in a Mannich-type reaction. Rearrangements enable the formation of a Schiff base from tryptamine, which then reacts with pyruvate in II to form a β-carboline carboxylic acid. The β-carboline carboxylic acid subsequently undergoes decarboxylation to produce 1-methyl β-carboline III. Hydroxylation followed by methylation in IV yields harmaline. The order of O-methylation and hydroxylation have been shown to be inconsequential to the formation of the harmaline intermediate.[7] In the last step V, the oxidation of harmaline is accompanied by the loss of water and effectively generates harmine.

Proposed biosynthesis of harmine from L-tryptophan

The difficulty distinguishing between L-tryptophan and free tryptamine as the precursor of harmine biosynthesis originates from the presence of the serotonin biosynthetic pathway, which closely resembles that of harmine, yet necessitates the availability of free tryptamine as its precursor.[7] As such, it is unclear if the decarboxylation of L-tryptophan, or the incorporation of pyruvate into the basic tryptamine structure is the first step of harmine biosynthesis. However, feeding experiments involving the feeding of one of tryptamine to hairy root cultures of P. harmala showed that the feeding of tryptamine yielded a great increase in serotonin levels with little to no effect on β-carboline levels, confirming that tryptamine is the precursor for serotonin, and indicating that it is likely only an intermediate in the biosynthesis of harmine; otherwise, comparable increases in harmine levels would have been observed.[8]

Uses

Monoamine oxidase inhibitor

Harmine is a RIMA, as it reversibly inhibits monoamine oxidase A (MAO-A), but not MAO-B.[4] Oral or intravenous harmine doses ranging from 30 to 300 mg may cause agitation, bradycardia or tachycardia, blurred vision, hypotension, paresthesias. Serum or plasma harmine concentrations may be measured as a confirmation of diagnosis. The plasma elimination half-life of harmine is on the order of 1–3 hours.[9]

Medically significant amounts of harmine occur in the plants Syrian rue and Banisteriopsis caapi. These plants also contain notable amounts of harmaline,[3] which is also a RIMA.[4] The psychoactive ayahuasca brew is made from B. caapi stem bark usually in combination with dimethyltryptamine (DMT) containing Psychotria viridis leaves. DMT is a psychedelic drug, but it is not orally active unless it is ingested with MAOIs. This makes harmine a vital component of the ayahuasca brew with regard to its ability to induce a psychedelic experience.[10] Syrian rue or synthetic harmine is sometimes used to substitute B. caapi in the oral use of DMT.[11]

Other

Harmaline and harmine fluoresce under ultraviolet light. These three extractions indicate that the middle one has a higher concentration of the two compounds.

Harmine is a useful fluorescent pH indicator. As the pH of its local environment increases, the fluorescence emission of harmine decreases. Due to its MAO-A specific binding, carbon-11 labeled harmine can be used in positron emission tomography to study MAO-A dysregulation in several psychiatric and neurologic illnesses.[12] Harmine was used as an antiparkinsonian medication since the late 1920s until the early 1950s. It was replaced by other medications.[13]

Research

Pancreatic islet cell proliferation

Harmine is currently the only known drug that induces proliferation (rapid mitosis and subsequent mass growth) of pancreatic alpha (α) and beta (β) cells in adult humans.[14] These islet sub-cells are normally resistant to growth stimulation in the adult stage of a human's life, as the cell mass plateaus at around age 10 and remains virtually unchanged.

Adverse effects

Harmine has been found to be relatively toxic[15] to humans where symptoms arise at 3mg/kg. These symptoms include behavioral changes such as sleep, tremors, gastrointestinal issues, nausea and vomiting.[citation needed]

Natural sources

Harmine is found in a wide variety of different organisms, most of which are plants.

Alexander Shulgin lists about thirty different species known to contain harmine, including seven species of butterfly in the family Nymphalidae.[16]

The harmine-containing plants include tobacco, Peganum harmala, two species of passiflora, and numerous others. Lemon balm (Melissa officinalis) contains harmine.[17]

In addition to B. caapi, at least three members of the Malpighiaceae contain harmine, including two more Banisteriopsis species and the plant Callaeum antifebrile. Callaway, Brito and Neves (2005) found harmine levels of 0.31-8.43% in B. caapi samples.[18]

The family Zygophyllaceae, which P. harmala belongs to, contains at least two other harmine-bearing plants: Peganum nigellastrum and Zygophyllum fabago.

History

J. Fritzsche was the first to isolate and name harmine. He isolated it from the husks of Peganum harmala seeds in 1848. The related harmaline was already isolated and named by Fr. Göbel in 1837 from the same plant.[19][13] The pharmacology of harmine was not studied in detail until 1895.[13] The structures of harmine and harmaline were determined in 1927 by Richard Helmuth Fredrick Manske and colleagues.[20][21]

In 1905, the Colombian naturalist and chemist, Rafael Zerda-Bayón suggested the name telepathine to the then unknown hallucinogenic ingredient in ayahuasca brew.[3][13] "Telepathine" comes from "telepathy", as Zerda-Bayón believed that ayahuasca induced telepathic visions.[3][22] In 1923, the Colombian chemist, Guillermo Fischer-Cárdenas was the first to isolate harmine from Banisteriopsis caapi, which is an important herbal component of ayahuasca brew. He called the isolated harmine "telepathine".[3] This was solely to honor Zerda-Bayón, as Fischer-Cárdenas found that telepathine had only mild non-hallucinogenic effects in humans.[23] In 1925, Barriga Villalba, professor of chemistry at the University of Bogotá, isolated harmine from B. caapi, but named it "yajéine",[13] which in some texts is written as "yageine".[3] In 1927, F. Elger, who was a chemist working at Hoffmann-La Roche, isolated harmine from B. caapi. With the assistance of Professor Robert Robinson in Manchester, Elger showed that harmine (which was already isolated in 1848) was identical with telepathine and yajéine.[24][13] In 1928, Louis Lewin isolated harmine from B. caapi, and named it "banisterine",[25] but this supposedly novel compound was soon also shown to be harmine.[13]

Harmine was first patented by Jialin Wu and others who invented ways to produce new harmine derivatives with enhanced antitumor activity and lower toxicity to human nervous cells.[26]

Legal status

Australia

Harmala alkaloids are considered Schedule 9 prohibited substances under the Poisons Standard (October 2015).[27] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[27]

Exceptions are made when in herbs, or preparations, for therapeutic use such as: (a) containing 0.1 per cent or less of harmala alkaloids; or (b) in divided preparations containing 2 mg or less of harmala alkaloids per recommended daily dose.[27]

References

  1. ↑ 1.0 1.1 1.2 "Harmine - CAS 442-51-3". scbio.de. Santa Cruz Biotechnology, Inc.. http://www.scbio.de/datasheet-202644-harmine.html. 
  2. ↑ The Merck Index (1996). 12th edition
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson's Disease?". Movement Disorders Clinical Practice 3 (1): 19–26. 2015. doi:10.1002/mdc3.12242. PMID 30713897. 
  4. ↑ 4.0 4.1 4.2 "The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization". Frontiers in Pharmacology 7: 35. 2016. doi:10.3389/fphar.2016.00035. PMID 26973523. 
  5. ↑ "The simple β-carboline alkaloids". Phytochemistry 19 (8): 1573–1582. 1980. doi:10.1016/S0031-9422(00)83773-5. http://www.sciencedirect.com/science/article/pii/S0031942200837735. 
  6. ↑ "SciFinderⁿ Login". https://sso.cas.org/as/authorization.oauth2?response_type=code&client_id=scifinder-n&redirect_uri=https%3A%2F%2Fscifinder-n.cas.org%2Fpa%2Foidc%2Fcb&state=eyJ6aXAiOiJERUYiLCJhbGciOiJkaXIiLCJlbmMiOiJBMTI4Q0JDLUhTMjU2Iiwia2lkIjoiOW0iLCJzdWZmaXgiOiJPYUUxeEsuMTYzNjk1NzY3NSJ9..5wCwUVpvCohoxPuelNXYXA.FNzx1epEQU7XKLOIfKZw9sFA-B1xNTEJgrzQ3t6LTSZGpsIoqRWrKcfqzIvqUOHUkXhmsiLU0o-ToIDwBwtkRgCXCFGmriUzgjRjfYFFj_bV6D9Ecb8-EqZHjZ4UgJIq50LntW-yXQfE73B0Zup-Xg.hnJD-6Ednl699nsrpZYPiw&nonce=h0ZRbLU6gzzg6-oVhiSyO9fWRRA-jI4HtH1MHoWUARg&scope=openid%20address%20email%20phone%20profile&vnd_pi_requested_resource=https%3A%2F%2Fscifinder-n.cas.org%2FsearchDetail%2Fsubstance%2F618e06e87bbc3e6eeb0be381%2FsubstanceDetails&vnd_pi_application_name=SciFinder-nIDF. 
  7. ↑ 7.0 7.1 7.2 Berlin Jochen; Rugenhagen Christiane; Greidziak Norbert; Kuzovkina Inna; Witte Ludger; Wray Victor (1993). "Biosynthesis of Serotonin and Beta-carboline Alkaloids in Hairy Root Cultures of Peganum Harmala". Phytochemistry 33 (3): 593–97. doi:10.1016/0031-9422(93)85453-x. 
  8. ↑ 8.0 8.1 Nettleship Lesley; Slaytor Michael (1974). "Limitations of Feeding Experiments in Studying Alkaloid Biosynthesis in Peganum Harmala Callus Cultures". Phytochemistry 13 (4): 735–42. doi:10.1016/s0031-9422(00)91406-7. 
  9. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 727-728.
  10. ↑ "Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness". Current Neuropharmacology 17 (2): 108–128. 2019. doi:10.2174/1570159X16666180125095902. PMID 29366418. 
  11. ↑ "Toxicological Aspects and Determination of the Main Components of Ayahuasca: A Critical Review". Medicines 6 (4): 106. 2019. doi:10.3390/medicines6040106. PMID 31635364. 
  12. ↑ Nathalie Ginovart; Jeffrey H. Meyer; Anahita Boovariwala; Doug Hussey; Eugenii A. Rabiner; Sylvain Houle; Alan A. Wilson (2006). "Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain". Journal of Cerebral Blood Flow & Metabolism 26 (3): 330–344. doi:10.1038/sj.jcbfm.9600197. PMID 16079787. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Foley, Paul Bernard (2001). "V. Encephalitis lethargica: New strategies in the therapy of parkinsonism". Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism (PhD thesis). Bavarian Julius Maximilian University. pp. 166–180. Retrieved 2020-11-22.
  14. ↑ Wang, P. (2015). "Induction of human pancreatic beta cell replication by inhibitors of dual specificity tyrosine regulated kinase". Nature Medicine 21 (4): 383–388. doi:10.1038/nm.3820. PMID 25751815. 
  15. ↑ Marwat, Sarfaraz Khan; Rehman, Fazal ur (1 January 2011). "Chapter 70 - Medicinal and Pharmacological Potential of Harmala (Peganum harmala L.) Seeds" (in en). Nuts and Seeds in Health and Disease Prevention. Academic Press. pp. 585–599. doi:10.1016/B978-0-12-375688-6.10070-2. ISBN 9780123756886. https://www.sciencedirect.com/science/article/pii/B9780123756886100702. 
  16. ↑ TiHKAL: The Continuation. Transform Press. 1997. ISBN 0-9630096-9-9.  Pages 713–714
  17. ↑ Natalie Harrington (2012). "Harmala Alkaloids as Bee Signaling Chemicals". Journal of Student Research 1 (1): 23–32. doi:10.47611/jsr.v1i1.30. http://www.jofsr.com/index.php/path/article/view/30. 
  18. ↑ Callaway J. C.; Brito G. S.; Neves E. S. (2005). "Phytochemical analyses of Banisteriopsis caapi and Psychotria viridis". Journal of Psychoactive Drugs 37 (2): 145–150. doi:10.1080/02791072.2005.10399795. PMID 16149327. 
  19. ↑ "Bestandtheile der Samen von Peganum Harmala" (in en). Justus Liebigs Annalen der Chemie 64 (3): 360–369. 1848. doi:10.1002/jlac.18480640353. https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/jlac.18480640353. 
  20. ↑ "Harmine and harmaline. Part IX. A synthesis of harmaline". Journal of the Chemical Society: 1–14. 1927. doi:10.1039/JR9270000001. https://pubs.rsc.org/en/content/articlelanding/1927/jr/jr9270000001. 
  21. ↑ , Howard S."Method of treating chemical dependency using β-carboline alkaloids, derivatives and salts thereof" US patent 5591738, published 1997-01-07
  22. ↑ Baldo, Benjamin (1920). "Telepathy and Telepathine". American Druggist 68 (4): 15. https://www.samorini.it/doc1/alt_aut/ad/baldo-telepathy-and-telepathin.pdf. 
  23. ↑ Fischer-Cárdenas, Guillermo (1923). "V. Encephalitis lethargica: New strategies in the therapy of parkinsonism" (PDF). Estudio sobre el principio activo del Yagé (PhD). Universidad Nacional. Retrieved 2020-11-22.
  24. ↑ Elger, F. (1928). "Über das Vorkommen von Harmin in einer südamerikanischen Liane (Yagé)" (in en). Helvetica Chimica Acta 11 (1): 162–166. doi:10.1002/hlca.19280110113. https://onlinelibrary.wiley.com/doi/abs/10.1002/hlca.19280110113. 
  25. ↑ Schultes, RE (1982). "The beta-carboline Hallucinogens of South America". Journal of Psychoactive Drugs 14 (3): 205–220. doi:10.1080/02791072.1982.10471930. PMID 6754896. http://www.tandfonline.com/doi/abs/10.1080/02791072.1982.10471930. 
  26. ↑ Wu, Jialin; Qi Chen & Rihui Cao et al., "Harmine derivatives, intermediates used in their preparations, preparation processes and use thereof", EP patent 1634881, published 2006-03-15
  27. ↑ 27.0 27.1 27.2 Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534

External links



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