Chemistry:Mesembrine
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.[1][2][3][4]
Mesembrine has also been identified in Mesembryanthemum cordifolium, Delosperma echinatum, and Oscularia deltoides.[5]
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).[6] A concentrated mesembrine extract of Sceletium tortuosum may exert antidepressant effects by acting as a monoamine releasing agent.[7] As such, mesembrine likely plays a dominant role in the antidepressant effects of kanna.[8]
Rat studies have evaluated effects of kanna extract, finding analgesic and antidepressant potential.[9] No adverse results were noted for a commercial extract up to 5000 mg/kg daily in rats.[10]
Structure
Mesembrine was first isolated and characterized in 1957.[11] 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).[12]
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.
-Mesembrine.svg)
The first total synthesis of mesembrine was reported in 1965.[13] 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.[14] 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.
See also
- SNTX-2643
References
- ↑ Medicinal plants of the world: an illustrated scientific guide to important medicinal plants and their uses (Second ed.). CABI. 2017. p. 226. ISBN 978-1-78639-325-8.
- ↑ "Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review". Journal of Ethnopharmacology 50 (3): 119–130. March 1996. doi:10.1016/0378-8741(95)01342-3. PMID 8691846.
- ↑ "Mesembrine alkaloids: Review of their occurrence, chemistry, and pharmacology". Journal of Ethnopharmacology 195: 10–19. January 2017. doi:10.1016/j.jep.2016.12.004. PMID 27939420.
- ↑ "Mesembrine: The archetypal psycho-active Sceletium alkaloid". Phytochemistry 166. October 2019. doi:10.1016/j.phytochem.2019.112061. PMID 31299396. Bibcode: 2019PChem.166k2061M.
- ↑ "The Distribution of Mesembrine Alkaloids in Selected Taxa of the Mesembryanthemaceae and their Modification in the Sceletium Derived 'Kougoed'". Pharmaceutical Biology 36 (3): 173–179. January 1998. doi:10.1076/phbi.36.3.173.6350.
- ↑ "Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids". Journal of Ethnopharmacology 137 (3): 1124–1129. October 2011. doi:10.1016/j.jep.2011.07.035. PMID 21798331.
- ↑ "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology 177: 111–116. January 2016. doi:10.1016/j.jep.2015.11.034. PMID 26615766.
- ↑ "Review on plants with CNS-effects used in traditional South African medicine against mental diseases". Journal of Ethnopharmacology 119 (3): 513–537. October 2008. doi:10.1016/j.jep.2008.08.010. PMID 18775771.
- ↑ "Effects of Sceletium tortuosum in rats". Journal of Ethnopharmacology 155 (1): 731–735. August 2014. doi:10.1016/j.jep.2014.06.007. PMID 24930358.
- ↑ "A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats". Food and Chemical Toxicology 74: 190–199. December 2014. doi:10.1016/j.fct.2014.09.017. PMID 25301237.
- ↑ "[Alkaloids of Mesembryanthemum tortuosum]" (in German). Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft 290 (10): 441–448. October 1957. doi:10.1002/ardp.19572901002. PMID 13471008.
- ↑ "Absolute configuration of mesembrine and related alkaloids: X-ray analysis of 6-epimesembranol methiodide.". Journal of the Chemical Society B: Physical Organic: 1267–1271. 1970. doi:10.1039/J29700001267.
- ↑ "The total synthesis of (±)-mesembrine". Tetrahedron Letters 6 (52): 4847–4851. 1965. doi:10.1016/S0040-4039(01)89046-8.
- ↑ "Total synthesis of (+)-mesembrine by asymmetric synthesis with amino acid.". Tetrahedron Letters 12 (16): 1133–1136. January 1971. doi:10.1016/S0040-4039(01)96647-X.
Further reading
- "Alkaloids from Cassia carnaval speg.: cassaine and carnavaline (1)". Tetrahedron Letters 12: 1133–1137. March 1967. doi:10.1016/S0040-4039(01)96647-X. PMID 6046785.
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