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Loren Cardani - Sandbox

Included below are the sections I chose to revise from each article.

Gelsemine

Gelsemine (C₂₀H₂₂N₂O₂) is an indole alkaloid isolated from flowering plants of the genus Gelsemium, a plant native to the subtropical and tropical Americas, and southeast Asia, and is a highly toxic compound that acts as a paralytic, exposure to which can result in death. It has generally potent activity as an agonist of the mammalian glycine receptor, the activation of which leads to an inhibitory postsynaptic potential in neurons following chloride ion influx, and systemically, to muscle relaxation of varying intensity and deleterious effect. Despite its danger and toxicity, recent pharmacological research has suggested that the biological activities of this compound may offer opportunities for developing treatments related to xenobiotic or diet-induced oxidative stress, and of anxiety and other conditions, with ongoing research including attempts to identify safer derivatives and analogs to make use of gelsemine's beneficial effects.

Chemical synthesis

The chemical synthesis of gelsemine has been an active target of interest since the early 1990s, given its place among the alkaloids, and its complex structure (seven contiguous stereocenters and six rings). Although the full mechanism of its biosynthesis is still being investigated, many research groups have successfully synthesized it using chemical means. The first racemic total synthesis of gelsemine was in 1994, by W.N. Speckamp's group, with a remarkable first overall yield of 0.83% (given the subsequent range, prior to 2014, of 0.02-1.2%).

Reaction scheme for W.N. Speckamp's first racemic total synthesis of gelsemine.

Eight further total syntheses have been reported in the literature, including from the groups of A.P. Johnson in 1994, T. Fukuyama in 1996 and again in 2000, D.J. Hart in 1997, L.E. Overman in 1999, S.J. Danishefsky in 2002, and Y. Qin in 2012, with the latter Fukuyama group synthesis (31 steps, 0.86%) and the Qin group synthesis (25 steps, 1%) being asymmetric. A further asymmetric synthesis using an organocatalytic Diels–Alder approach from the F.G. Qiu and H. Zhai groups in China, reporting a remarkable 12 steps and a 5% yield, was reported in 2015. Additional synthetic approaches were discussed by notable scientists such as Fleming, Stork, Penkett, Pearson, Aubé, Vanderwal, and Simpkins.

Treatment

Gelsemine is a highly toxic and therefore possibly fatal substance for which there is no antidote, but the symptoms can be managed in low dose intoxications. In the case of an oral exposure a gastric lavage is performed, which must be done within approximately one hour of ingestion. Activated charcoal is then administered to bind the free toxin in the gastrointestinal tract to prevent absorption. Benzodiazepine or phenobarbital is also generally administered to help control seizing, and atropine can be used to treat bradycardia. Electrolyte and nutrient levels are monitored and controlled.

In the case of a skin exposure, the area is washed with soap and water for 15 minutes to avoid skin damage.

While there is no current treatment to reverse the effects of gelsemine poisoning, preliminary research done in rats has suggested that strychnine has potential therapeutic applications due to its antagonistic effects at the glycine receptor, resulting in a counteraction of some downstream effects such as the increase in allopregnanolone production associated with gelsemine poisoning.

Summary of biological activities

Full sections in following are devoted to specific activities of gelsemine. Noted are the facts that it is a highly toxic compound, where exposure can result in paralysis and death. It is reported to be a glycine receptor agonist with significantly higher binding affinity for some of these receptors than its native agonist, glycine. In addition, it has been shown to have effects on pathways/systems in model animals (rat, rabbit), related to xenobiotic- or diet-induced oxidative stress, and in the treatment of anxiety and other conditions.

History

Gelsimium extracts, and so gelsemine, indirectly, have been the subject of serious scientific study for over a hundred years. On the medical side, gelsemium tinctures were used in the treatment of neuralgia by physicians in England, in the late 19th century; Arthur Conan Doyle, the noted author who first trained as a physician, after observing the success of such treatments, ingested increasing doses of a tincture daily, to “ascertain how far one might go in taking the drug, and what the primary symptoms of an overdose might be,” submitting his first career publication on this in the British Medical Journal.^{[primary source]} On the chemistry side, the December 1910 meeting of the Division of Pharmaceutical Chemistry, of the American Chemical Society, reports among the papers read, the "Assay of Gelsemium" by L.E. Sayre.^{[primary source]}

Mechanisms of action

Gelsemine is an agonist for the glycine receptor (GlyR) with a much greater affinity for studied examples of this receptor than glycine. These receptors are ligand-gated ion channels which affect a variety of physiological processes. When glycine receptors are activated by agonist binding to at least two of the five agonist binding sites, chloride ions enter the neuron. This causes an inhibitory postsynaptic potential, which, systemically, leads to muscle relaxation.

Gelsemium Sempervirens

History

Homeopathy

Gelsemium sempervirens has been utilized since the 19th century as a folk remedy for various medical conditions, including neuralgia, migraines, uterine pain, rheumatism, anxiety, influenza, nausea, and whooping cough. This drug was made from the plant's rhizome and rootlets and was marketed under the name Gelsemium up until the beginning of the twentieth century. However, the alkaloids in the plant which are said to confer this activity have not been derivatized or represented in modern medicine, and the efficacy of Gelsemium sempervirens or any of its component alkaloids is still a topic of debate. Small oral doses of Gelsemium sempervirens have been shown to reduce anxiety, depression, and pain in mouse models, and in neurocytes, it has demonstrated the ability to affect the expression of several genes, primarily those involved in brain function. It is still unclear whether these effects would extend to human patients.

note: I had not proposed to do this, but I felt like I had to add a section here:

Toxicity Biological Activity

Toxicity

All parts of this plant contain the toxic strychnine-related alkaloids gelsemine and gelseminine and should not be consumed. The sap may cause skin irritation in sensitive individuals. Children, mistaking this flower for honeysuckle, have been poisoned by sucking the nectar from the flower. The nectar is also toxic to honeybees, which may cause brood death when gathered by the bees. The nectar may, however, be beneficial to bumblebees. It has been shown that bumblebees fed on gelsemine have a reduced load of Crithidia bombi in their fecal matter after 7 days, although this difference was not significant after 10 days. Reduced parasite load increases foraging efficiency, and pollinators may selectively collect otherwise toxic secondary metabolites as a means of self-medication.

The plant can be lethal to livestock.

Applications in medicine

Gelsemine, despite its toxicity, has been shown to decrease anxiety in homeopathic doses.

Koumine and yohimbane, two other alkaloids found in Gelsemium sempervirens, have demonstrated moderate anti-tumor activity in early cell studies. Koumine has also been shown to demonstrate analgesic and anti-inflammatory properties.

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