mesembrine
{{Short description|Chemical compound}}
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| image = Mesembrine.svg
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| caption = Above: molecular structure of mesembrine
Below: 3D representation of a mesembrine molecule
| image2 = Mesembrine 3D.png
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| class = Serotonin reuptake inhibitor; PDE4 inhibitor
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| CAS_number = 468-53-1
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| PubChem = 394162
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| ChemSpiderID = 349381
| UNII = P5X28MLQ1Z
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| IUPAC_name = (3aS,7aS)-3a-(3,4-Dimethoxyphenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindol-6-one
| chemical_formula =
| C = 17
| H = 23
| N = 1
| O = 3
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| SMILES = CN1CC[C@@]2([C@H]1CC(=O)CC2)C3=CC(=C(C=C3)OC)OC
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| StdInChI = 1S/C17H23NO3/c1-18-9-8-17(7-6-13(19)11-16(17)18)12-4-5-14(20-2)15(10-12)21-3/h4-5,10,16H,6-9,11H2,1-3H3/t16-,17-/m1/s1
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| StdInChIKey = DAHIQPJTGIHDGO-IAGOWNOFSA-N
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Mesembrine is an alkaloid primarily derived from the plant Sceletium tortuosum, commonly known as kanna. This compound is noted for its psychoactive properties, particularly as a serotonin reuptake inhibitor, which contributes to its potential use in treating mood disorders and anxiety. Mesembrine has garnered interest in both traditional medicine and modern pharmacology, where it is explored for its effects on enhancing mood and cognitive function.
Kanna itself has a long history of use by indigenous peoples in southern Africa, who utilized it for its mood-enhancing and stress-relieving effects, often consuming it in various forms such as teas or chews.{{cite book | vauthors = Van Wyk BE, Wink M |title=Medicinal plants of the world: an illustrated scientific guide to important medicinal plants and their uses |date=2017 |publisher=CABI |isbn=978-1-78639-325-8 |edition=Second | page = 226 }}{{cite journal | vauthors = Smith MT, Crouch NR, Gericke N, Hirst M | title = Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review | journal = Journal of Ethnopharmacology | volume = 50 | issue = 3 | pages = 119–130 | date = March 1996 | pmid = 8691846 | doi = 10.1016/0378-8741(95)01342-3 | type = Review }}{{cite journal | vauthors = Krstenansky JL | title = Mesembrine alkaloids: Review of their occurrence, chemistry, and pharmacology | journal = Journal of Ethnopharmacology | volume = 195 | issue = | pages = 10–19 | date = January 2017 | pmid = 27939420 | doi = 10.1016/j.jep.2016.12.004 | type = Review }}{{cite journal | vauthors = Makolo F, Viljoen A, Veale CG | title = Mesembrine: The archetypal psycho-active Sceletium alkaloid | journal = Phytochemistry | volume = 166 | issue = | pages = 112061 | date = October 2019 | pmid = 31299396 | doi = 10.1016/j.phytochem.2019.112061 | type = Review }}
Mesembrine has also been identified in Mesembryanthemum cordifolium, Delosperma echinatum, and Oscularia deltoides.{{cite journal | vauthors = Smith MT, Field CR, Crouch NR, Hirst M | title=The Distribution of Mesembrine Alkaloids in Selected Taxa of the Mesembryanthemaceae and their Modification in the Sceletium Derived 'Kougoed' | journal=Pharmaceutical Biology | date=January 1998 | volume=36 | issue=3 | pages=173–179 | doi=10.1076/phbi.36.3.173.6350 | doi-access=free }}
Pharmacology
Mesembrine has been shown to act as a serotonin reuptake inhibitor (Ki = 1.4 nM), and has also been found to behave as a weak inhibitor of the enzyme phosphodiesterase 4 (PDE4) (Ki = 7,800 nM).{{cite journal | vauthors = Harvey AL, Young LC, Viljoen AM, Gericke NP | title = Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids | journal = Journal of Ethnopharmacology | volume = 137 | issue = 3 | pages = 1124–1129 | date = October 2011 | pmid = 21798331 | doi = 10.1016/j.jep.2011.07.035 }} A concentrated mesembrine extract of Sceletium tortuosum may exert antidepressant effects by acting as a monoamine releasing agent.{{cite journal | vauthors = Coetzee DD, López V, Smith C | title = High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor | journal = Journal of Ethnopharmacology | volume = 177 | pages = 111–116 | date = January 2016 | pmid = 26615766 | doi = 10.1016/j.jep.2015.11.034 }} As such, mesembrine likely plays a dominant role in the antidepressant effects of kanna.{{cite journal | vauthors = Stafford GI, Pedersen ME, van Staden J, Jäger AK | title = Review on plants with CNS-effects used in traditional South African medicine against mental diseases | journal = Journal of Ethnopharmacology | volume = 119 | issue = 3 | pages = 513–537 | date = October 2008 | pmid = 18775771 | doi = 10.1016/j.jep.2008.08.010 }}
Rat studies have evaluated effects of kanna extract, finding analgesic and antidepressant potential.{{cite journal | vauthors = Loria MJ, Ali Z, Abe N, Sufka KJ, Khan IA | title = Effects of Sceletium tortuosum in rats | journal = Journal of Ethnopharmacology | volume = 155 | issue = 1 | pages = 731–735 | date = August 2014 | pmid = 24930358 | doi = 10.1016/j.jep.2014.06.007 }} No adverse results were noted for a commercial extract up to 5000 mg/kg daily in rats.{{cite journal | vauthors = Murbach TS, Hirka G, Szakonyiné IP, Gericke N, Endres JR | title = A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats | journal = Food and Chemical Toxicology | volume = 74 | pages = 190–199 | date = December 2014 | pmid = 25301237 | doi = 10.1016/j.fct.2014.09.017 | doi-access = free }}
Structure
Mesembrine was first isolated and characterized in 1957.{{cite journal | vauthors = Bodendorf K, Krieger W | title = [Alkaloids of Mesembryanthemum tortuosum] | language = German | journal = Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft | volume = 290 | issue = 10 | pages = 441–448 | date = October 1957 | pmid = 13471008 | doi = 10.1002/ardp.19572901002 }} It is a tricyclic molecule with two bridgehead chiral carbons located between the five-membered and six-membered rings. The naturally occurring form of mesembrine produced by plants is the levorotatory isomer, (−)-mesembrine, where the carbon atoms at positions 3a and 7a both have the S configuration (3aS,7aS).{{cite journal | vauthors = Coggon P, Farrier DS, Jeffs PW, McPhail AT | title = Absolute configuration of mesembrine and related alkaloids: X-ray analysis of 6-epimesembranol methiodide. | journal = Journal of the Chemical Society B: Physical Organic | pages = 1267–1271| year = 1970 | doi = 10.1039/J29700001267 }}
Total synthesis
Because of its structure and bioactivity, mesembrine has been a target for total synthesis over the past 40 years. Over 40 total syntheses have been reported for mesembrine, most of which focused on different approaches and strategies for the construction of the bicyclic ring system and the quaternary carbon.
File:Shamma’s route for total synthesis of (±)-Mesembrine.svg
File:Yamada’s asymmetric total synthesis of Mesembrine.svg
The first total synthesis of mesembrine was reported in 1965.{{cite journal |vauthors=Shamma M, Rodriguez HR |date=1965 |title=The total synthesis of (±)-mesembrine |journal=Tetrahedron Letters |volume=6 |issue=52 |pages=4847–4851 |doi=10.1016/S0040-4039(01)89046-8}} This route has 21 steps, which was among the longest synthetic routes for mesembrine. Key steps involve the construction of the six-membered ketone ring by Diels–Alder reaction, α-allylation for synthesis of the quaternary carbon, and conjugate addition reaction for the final five-membered ring closure. The final product from this route is a racemic mixture of (+)- and (-)-mesembrine.
In 1971, first asymmetric total synthesis of (+)-mesembrine was reported.{{cite journal |vauthors=Yamada SI, Otani G |date=January 1971 |title=Total synthesis of (+)-mesembrine by asymmetric synthesis with amino acid. |journal=Tetrahedron Letters |volume=12 |issue=16 |pages=1133-1136 |doi=10.1016/S0040-4039(01)96647-X}} This synthesis introduced the quaternary carbon atom through an asymmetric Robinson annulation reaction, which was mediated by a chiral auxiliary derived from L-proline. In the final step, an intramolecular aza-Michael addition produced the fused pyrrolidine ring system.
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References
{{Reflist|2}}
Further reading
{{refbegin}}
- {{cite journal | vauthors = Lythgoe D, Vernengo MJ | title = Alkaloids from Cassia carnaval speg.: cassaine and carnavaline (1) | journal = Tetrahedron Letters | volume = 12 | pages = 1133–1137 | date = March 1967 | pmid = 6046785 | doi = 10.1016/S0040-4039(01)96647-X }}
{{refend}}
{{Monoamine reuptake inhibitors}}
{{Phosphodiesterase inhibitors}}
Category:Monoamine releasing agents