Mesembrine

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). A concentrated mesembrine extract of Sceletium tortuosum may exert antidepressant effects by acting as a monoamine releasing agent. As such, mesembrine likely plays a dominant role in the antidepressant effects of kanna.

Rat studies have evaluated effects of kanna extract, finding analgesic and antidepressant potential. No adverse results were noted for a commercial extract up to 5000 mg/kg daily in rats.

Structure

Mesembrine was first isolated and characterized in 1957. 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).

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.

The first total synthesis of mesembrine was reported in 1965. 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. 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.

References

References

1. (2017). "Medicinal plants of the world: an illustrated scientific guide to important medicinal plants and their uses". CABI.
2. (March 1996). "Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review". Journal of Ethnopharmacology.
3. (January 2017). "Mesembrine alkaloids: Review of their occurrence, chemistry, and pharmacology". Journal of Ethnopharmacology.
4. (October 2019). "Mesembrine: The archetypal psycho-active Sceletium alkaloid". Phytochemistry.
5. (January 1998). "The Distribution of Mesembrine Alkaloids in Selected Taxa of the Mesembryanthemaceae and their Modification in the Sceletium Derived 'Kougoed'". Pharmaceutical Biology.
6. (October 2011). "Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids". Journal of Ethnopharmacology.
7. (January 2016). "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology.
8. (October 2008). "Review on plants with CNS-effects used in traditional South African medicine against mental diseases". Journal of Ethnopharmacology.
9. (August 2014). "Effects of Sceletium tortuosum in rats". Journal of Ethnopharmacology.
10. (December 2014). "A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats". Food and Chemical Toxicology.
11. (October 1957). "[Alkaloids of Mesembryanthemum tortuosum]". Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft.
12. (1970). "Absolute configuration of mesembrine and related alkaloids: X-ray analysis of 6-epimesembranol methiodide.". Journal of the Chemical Society B: Physical Organic.
13. (1965). "The total synthesis of (±)-mesembrine". Tetrahedron Letters.
14. (January 1971). "Total synthesis of (+)-mesembrine by asymmetric synthesis with amino acid.". Tetrahedron Letters.