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. 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. Gelsemine is found in, and can be isolated from, the subtropical to tropical flowering plant genus Gelsemium, family Loganiaceae, which as of 2014 included five species, where G. sempervirens Ait., the type species, is prevalent in the Americas and G. elegans Benth. in China and East Asia, The species in the Americas, G. sempervirans, has a number of common names that include yellow or Carolina jasmine (or jessamine), gelsemium, evening trumpetflower, and woodbine. The plant genus is native to the subtropical and tropical Americas, e.g., in Mexico, Honduras, Guatemala, and Belize, as well as to China and southeast Asia. The species is prized for its 'heavily fragrant yellow flowers,' and has been cultivated since mid-seventeenth century (in Europe). It is found in southeastern and south-central states of the U.S., and as a garden plant in warmer areas where it can be trained to grow over arbors or to cover walls (see image). All plant parts of the herbage and exudates of this genus, including its sap and nectar, appear to contain gelsemine and related compounds, as well as a wide variety of further alkaloids and other natural products. The plant's herbage, in particular, is known to contain several toxic alkaloids, and is generally known to be poisonous to livestock and humans. Gelsemine was isolated from G. sempervirens Ait., in 1870. Its chemical formula was determined to be C20H22N2O2, thus with a molecular weight of 322.44 g/mol. Its structure was finally determined, by X-ray crystallographic analysis and by nuclear magnetic resonance (NMR) spectroscopy, in 1959 by Conroy and Chakrabarti. It is a monoterpenoid type of indole alkaloid, and a close relative of the natural product gelseminine, which is also present from the same natural sources. The gelsemine class of alkaloids are some of a wide variety of the alkaloid and other natural products that have been isolated from this genus of plants. Gelsemine's biosynthesis, as of 1998, is thought to proceed from 3α(S)-strictosidine (isovincoside), the common precursor for essentially all monoterpenoid indole alkaloids—itself deriving directly from mevalonic acid-derived secologanin and tryptamine.:p. 629 From strictosidine, the biosynthesis proceeds through five intermediates—including koumicine (akkuammidine), koumidine, vobasindiol, anhydrovobasindiol, and gelsenidine (humantienine-type).:p. 629 The related alkaloids koumine and gelsemicine also derive from this pathway (koumine from anhydrovobasindiol via oxidation and rearrangement, and gelsemicine from gelsemine itself, via aromatic oxidation and O-methylation).:p. 629 :p. 132ffFor the chemical synthesis (natural product synthesis, studies and total synthesis), see the separate section below. 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. 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. 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. Gelsemine is an agonist for the glycine receptor (GlyR) with a much greater affinity for studied examples of this receptor than glycine. When glycine receptors are activated, chloride ions enter the neuron causing an inhibitory postsynaptic potential, which, systemically, leads to muscle relaxation.