Mesembrine Explained

Width:160px
Class:Serotonin reuptake inhibitor
PDE4 inhibitor
Legal Us:Unscheduled
Cas Number:468-53-1
Pubchem:394162
Chemspiderid:349381
Unii:P5X28MLQ1Z
Iupac Name:(3aS,7aS)-3a-(3,4-Dimethoxyphenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindol-6-one
C:17
H:23
N:1
O:3
Smiles:CN1CC[C@@]2([C@H]1CC(=O)CC2)C3=CC(=C(C=C3)OC)OC
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
Stdinchikey:DAHIQPJTGIHDGO-IAGOWNOFSA-N

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. The plant 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 by Bodendorf et al. 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.

The first total synthesis of mesembrine was reported by Shamma, et al.[13] 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, Yamada et al.[14] reported the first asymmetric total synthesis of (+)-mesembrine. 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.

Further reading

Notes and References

  1. Book: Van Wyk BE, Wink M . Medicinal plants of the world: an illustrated scientific guide to important medicina plants and theier uses . 2017 . CABI . 978-1-78639-325-8 . Second . 226 .
  2. Smith MT, Crouch NR, Gericke N, Hirst M . Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review . Journal of Ethnopharmacology . 50 . 3 . 119–130 . March 1996 . 8691846 . 10.1016/0378-8741(95)01342-3 . Review .
  3. Krstenansky JL . Mesembrine alkaloids: Review of their occurrence, chemistry, and pharmacology . Journal of Ethnopharmacology . 195 . 10–19 . January 2017 . 27939420 . 10.1016/j.jep.2016.12.004 . Review .
  4. Makolo F, Viljoen A, Veale CG . Mesembrine: The archetypal psycho-active Sceletium alkaloid . Phytochemistry . 166 . 112061 . October 2019 . 31299396 . 10.1016/j.phytochem.2019.112061 . Review .
  5. Smith MT, Field CR, Crouch NR, Hirst M . The Distribution of Mesembrine Alkaloids in Selected Taxa of the Mesembryanthemaceae and their Modification in the Sceletium Derived 'Kougoed' . Pharmaceutical Biology . January 1998 . 36 . 3 . 173–179 . 10.1076/phbi.36.3.173.6350 . free .
  6. Harvey AL, Young LC, Viljoen AM, Gericke NP . 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 . 21798331 . 10.1016/j.jep.2011.07.035 .
  7. Coetzee DD, López V, Smith C . 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 . 26615766 . 10.1016/j.jep.2015.11.034 .
  8. Stafford GI, Pedersen ME, van Staden J, Jäger AK . Review on plants with CNS-effects used in traditional South African medicine against mental diseases . Journal of Ethnopharmacology . 119 . 3 . 513–537 . October 2008 . 18775771 . 10.1016/j.jep.2008.08.010 .
  9. Loria MJ, Ali Z, Abe N, Sufka KJ, Khan IA . Effects of Sceletium tortuosum in rats . Journal of Ethnopharmacology . 155 . 1 . 731–735 . August 2014 . 24930358 . 10.1016/j.jep.2014.06.007 .
  10. Murbach TS, Hirka G, Szakonyiné IP, Gericke N, Endres JR . A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats . Food and Chemical Toxicology . 74 . 190–199 . December 2014 . 25301237 . 10.1016/j.fct.2014.09.017 . free .
  11. Bodendorf K, Krieger W . [Alkaloids of Mesembryanthemum tortuosum] . German . Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft . 290 . 10 . 441–448 . October 1957 . 13471008 . 10.1002/ardp.19572901002 .
  12. Coggon P, Farrier DS, Jeffs PW, McPhail AT . 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 . 10.1039/J29700001267 .
  13. The total synthesis of (±)-mesembrine . 1965 . Shamma M, Rodriguez HR . Tetrahedron Letters . 6 . 52 . 4847–4851 . 10.1016/S0040-4039(01)89046-8 .
  14. Yamada SI, Otani G . Total synthesis of (+)-mesembrine by asymmetric synthesis with amino acid. . Tetrahedron Letters . January 1971 . 12 . 16 . 1133-1136 . 10.1016/S0040-4039(01)96647-X .

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