Mesembrine is an

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...

present in ''

Sceletium tortuosum Sceletium tortuosum is a succulent plant commonly found in South Africa, which is also known as Kanna, Channa, Kougoed (Kauwgoed/ 'kougoed', prepared from 'fermenting' ''S. tortuosum'')—which literally means, 'chew(able) things' or 'something ...

'' (kanna). It has been shown to act as a

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...

(K_i = 1.4 nM), and more recently, has also been found to behave as a weak

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

phosphodiesterase 4 At least four types of the enzyme phosphodiesterase 4 (PDE4) are known: * PDE4A * PDE4B * PDE4C * PDE4D See also * 3',5'-cyclic-AMP phosphodiesterase * Phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond ...

(PDE4) (K_i = 7,800 nM). Still more recently, in an in vitro study published in 2015, scientist concluded that "a high-mesembrine Sceletium extract exerts its anti-depressant effect by acting primarily as

monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of ...

, rather than as selective serotonin-reuptake inhibitor." As such, mesembrine likely plays a dominant role in the

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...

effects of kanna. The levorotatory isomer, (−)-mesembrine, is the natural form. 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. Mesembrine has also been identified in Mesembryanthemum cordifolium,

Delosperma echinatum ''Delosperma echinatum'' is a succulent plant, native to South Africa. It is also known as the pickle plant. The new genus ''Delosperma'' was erected by English botanist N. E. Brown in 1925, with this species later acknowledged as the type spe ...

and Oscularia deltoides

Total synthesis

Mesembrine was first isolated and characterized by Bodendorf, ''et al.'' in 1957. It is a

tricyclic Tricyclics are chemical compounds that contain three interconnected rings of atoms. Many compounds have a tricyclic structure, but in pharmacology, the term has traditionally been reserved to describe heterocyclic drugs. Among these are antid ...

molecule and has two bridgehead

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

carbons between the five-membered ring and the six-membered ring (highlighted in green in the figure below). Because of its structure and bioactivity, mesembrine has been a target for

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...

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 A quaternary carbon is a carbon atom bound to four other carbon atoms. For this reason, quaternary carbon atoms are found only in hydrocarbons having at least five carbon atoms. Quaternary carbon atoms can occur in branched alkanes, but not in li ...

The first total synthesis of mesembrine was reported by Shamma, ''et al.'' 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 In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

of (+)- and (-)-mesembrine. Shamma’s route for total synthesis of (±)-Mesembrine

In 1971, Yamada, ''et al.''Yamada, S; Otani, G. Tetrahedron Lett. 1971, 12, 1133. reported the first asymmetric total synthesis of (+)-mesembrine. The quaternary carbon was introduced by asymmetric

Robinson annulation The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds. The method uses a keto ...

reaction mediated by an L-proline derivative. Yamada’s asymmetric total synthesis of (±)-Mesembrine

References

{{Phosphodiesterase inhibitors Antidepressants Indole alkaloids Ketones Phenol ethers PDE4 inhibitors Serotonin reuptake inhibitors Total synthesis