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Drug class | Serotonin reuptake inhibitor; PDE4 inhibitor |
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Formula | C17H23NO3 |
Molar mass | 289.375 g·mol−1 |
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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. 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]
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]
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]
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.
β-Carboline (9H-pyrido[3,4-b]indole) represents the basic chemical structure for more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines primarily influence brain functions but can also exhibit antioxidant effects. Synthetically designed β-carboline derivatives have recently been shown to have neuroprotective, cognitive enhancing and anti-cancer properties.
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.
Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum. Hyperforin may be involved in the pharmacological effects of St. John's wort, specifically in its antidepressant effects.
Mesembryanthemum tortuosum is a succulent plant in the family Aizoaceae native to the Cape Provinces of South Africa. It is known as the Namaqua skeletonfig, kanna, channa, kougoed —which literally means, 'chew(able) things' or 'something to chew'.
The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene. SLC18A2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.
Aporphine is an alkaloid with the chemical formula C17H17N. It is the core chemical substructure of the aporphine alkaloids, a subclass of quinoline alkaloids. It can exist in either of two enantiomeric forms, (R)-aporphine and (S)-aporphine.
A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.
A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.
Mesembryanthemum cordifolium, formerly known as Aptenia cordifolia, is a species of succulent plant in the iceplant family. It is a creeping plant that forms a carpet of flat-growing perennial herbs in groups on the ground from a base. The genus name means middle-embryo flower in reference to the position of the ovary in the flower. The specific epithet is derived from Latin for heart-shaped leaves.
Dauricine is a plant metabolite, chemically classified as a phenol, an aromatic ether, and an isoquinoline alkaloid. It has been isolated from the Asian vine Menispermum dauricum, commonly known as Asian moonseed, and the North American vine Menispermum canadense, commonly known as Canadian moonseed. Scientists Tetsuji Kametani and Keiichiro Fukumoto of Japan are credited with being the first to synthesize dauricine in 1964, using both the Arndt-Eistert reaction and Bischler-Napieralski reaction to do so. Dauricine has been studied in vitro for its potential to inhibit cancer cell growth and to block cardiac transmembrane Na+, K+, and Ca2+ ion currents.
JNJ-7925476 is a triple reuptake inhibitor antidepressant discovered by Johnson & Johnson, but never marketed.
A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.
Bakuchiol is a meroterpenoid in the class terpenophenol.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
Mesembrenone is an alkaloid constituent of Sceletium tortuosum (Kanna) and minor constituent of Lampranthus aureus and Lampranthus spectabilis.
Tortuosamine is an alkaloid found in Sceletium tortuosum.
Juncusol is a 9,10-dihydrophrenathrene found in Juncus species such as J. acutus, J. effusus or J. roemerianus.
Fascaplysin is a marine alkaloid based on 12H-pyrido[1–2-a:3,4-b′]diindole ring system. It was first isolated as a red pigment from the marine sponge Fascaplysinopsis reticulata that was collected in the South Pacific near Fiji in 1988. Fascaplysin possesses a broad range of in vitro biological activities including analgesic, antimicrobial, antifungal, antiviral, antimalarial, anti-angiogenic, and antiproliferative activity against numerous cancer cell lines.
Drosanthemum hispidum, the hairy dewflower, is a species of perennial herb in the family Aizoaceae. They are succulent plants and have a self-supporting growth form and simple, broad leaves. Flowers are visited by Colletes schultzei.
Lampranthus spectabilis, the trailing iceplant, is a species of flowering plant in the family Aizoaceae, native to the Cape Provinces of South Africa. The unimproved species and a number of cultivars are commercially available, including 'Tresco Apricot', 'Tresco Brilliant', 'Tresco Fire', 'Tresco Orange', 'Tresco Peach', 'Tresco Pearl', 'Tresco Purple', and 'Tresco Red'.