Gelsemine

Systematic (IUPAC) name
3-ethenyl-1-methyl-2,3,3a,7,8,8a-hexahydro-1h,5h-spiro[3,8,5-(ethane[1,1,2]triyl)oxepino[4,5-b]pyrrole-4,3'-indol]-2'(1'h)-one
Identifiers
CAS Number	509-15-9
ATC code	none
PubChem	CID: 279057
Chemical data
Formula	C20H22N2O2
Molecular mass	322.40 g/mol
SMILES CN1C(C2CO3)[C@@H]4[C@]5(C(C=CC=C6)=C6NC5=O)[C@H]3C[C@H]2[C@]4(C=C)C1

Gelsemine (C20H22N2O2) is an alkaloid that comes from the flowering plant, Gelsemium sempervirens, and is a highly toxic compound that acts as a paralytic and often results in death. It acts as an agonist for the glycine receptor with a significantly higher binding affinity than glycine. Recent pharmacological research has suggested that this compound can be effective in the treatment of anxiety and other conditions, and is searching for a safe way to utilize these beneficial effects.

History

While Arthur Conan Doyle is most commonly known as the mastermind behind Sherlock Holmes, he also was a doctor with a similar madness to that of Sherlock’s. Doyle’s first academic publication was concerning the effects of Gelsemium intoxication in humans. After observing the successful treatment of a gelsemium tincture for neuralgia, he became determined to “ascertain how far one might go in taking the drug, and what the primary symptoms of an overdose might be.” To do this, Doyle ingested increasing doses of his prepared tincture every day and published his results in the British Medical Journal. He determined that an adult could safely ingest up to 90 minims of the gelsemium tincture (1 minim = 1/480 fluid ounces).

Synthesis

The biosynthesis of gelsemine is unknown, and synthetic synthesis proved difficult due to its complex structure containing seven stereocenters and five rings. Progress made with this molecule since its isolation in 1870. It has been synthesized nine times since 1994 by Speckamp (1994), Johnson (1994), Hart (1994), Fukuyama (1996), Overman (1999), Fukuyama (2000), Danishefsky (2002), Qin (2012), and Qiu (2015). There are three enantioselective 2000, 2012, and 2015 syntheses are reported.

Toxicology

Gelsemine has a molecular weight of 322.44 g/mol, and can be administered via ingestion or injection (subcutaneous or intraperitoneal). Its high toxicity prevents study to determine LD50 in humans, but it has been shown to have LD50s of 49 mg/kg intraperitoneal in mice and 0.1 mg/kg subcutaneous in rabbits.

Mechanism of Action and Symptoms

Gelsemine is an agonist for the glycine receptor (GlyR) with a much larger affinity for the receptor than glycine. When glycine receptors are activated, chloride ions enter the neuron causing an inhibitory postsynaptic potential, which causes muscle relaxation. At lower doses this inhibition can cause nausea, diarrhea and muscle spasms caused by the loss of control of involuntary muscle control. Higher doses cause vision impairment or blindness, paralysis, and death.

Many sources have linked gelsemine with a similar alkaloid that interacts with GlyR, strychnine. It should be noted that strychnine is an antagonist of GlyR, making it a stimulatory molecule leading to dramatic muscle seizing. These two molecules work on opposition to each other.

Medicinal Applications

Gelsemium sempervirens

Although gelsemine has no historical uses as anything but a poison, the plant it comes from, Gelsemium sempervirens, has been utilized for a variety of ailments. It should be noted, though, that this plant is also toxic and there are serious safety concerns in its use. Historically, Gelsemium tinctures have been a go-to treatment for a large variety of ailments. It has been utilized to treat acne and other papular eruption, anxiety, ear pain, migraine, diseases causing a large inflammatory response and in situations where someone is experiencing abnormal nervous functions (paralysis, “pins and needles” feeling, neuralgia, etc).

Therapeutic Potential

Although gelsemine is highly toxic, it has been recognized to have therapeutic properties. Recent research has been investigating these properties in order to develop a safer gelsemine-derivative to treat a variety of disorders. The anxiolytic effects of Gelsemium sempervirens is due to gelsemine, and can be more effective in treating anxiety than Diazepam. Gelsemine has also been found to have protective effects against oxidative stress by reducing oxidase activity and increasing anti-oxidant synthesis.

Treatment

Gelsemine is a highly toxic and typically 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 will also be administered to help control seizing, and atropine can be used to treat bradycardia. Electrolyte and nutrient levels should be monitored and controlled. In the case of a skin exposure, the area should be washed wish soap and water for 15 minutes to avoid dermal damage.

While there is no current treatment to reverse the effects of gelsemine poisoning, preliminary research has suggested that strychnine has potential therapeutic applications due to its antagonistic effects on the glycine receptor.

See also

• Gelsemium sempervirens
• Strychnine
• Glycine receptor antagonists
• Alkaloids