Strychnine

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For the song by The Sonics, see Here Are the Sonics.
Strychnine
Names
IUPAC name
Strychnidin-10-one[1]
Systematic IUPAC name
(4bR,4b1S,7aS,8aR,8a1R,12aS)-4b1,5,6,7a,8,8a,8a1,11,12a,13-Decahydro-14H-12-oxa-7,14a-diaza-7,9-methanocyclohepta[cd]cyclopenta[g]fluoranthen-14-one
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.000.290 Edit this at Wikidata
IUPHAR/BPS
KEGG
RTECS number
  • WL2275000
UNII
UN number 1692
  • InChI=1S/C21H22N2O2/c24-18-10-16-19-13-9-17-21(6-7-22(17)11-12(13)5-8-25-16)14-3-1-2-4-15(14)23(18)20(19)21/h1-5,13,16-17,19-20H,6-11H2/t13-,16-,17-,19-,20-,21+/m0/s1 checkY
    Key: QMGVPVSNSZLJIA-FVWCLLPLSA-N checkY
  • InChI=1/C21H22N2O2/c24-18-10-16-19-13-9-17-21(6-7-22(17)11-12(13)5-8-25-16)14-3-1-2-4-15(14)23(18)20(19)21/h1-5,13,16-17,19-20H,6-11H2/t13-,16-,17-,19-,20-,21+/m0/s1
    Key: QMGVPVSNSZLJIA-FVWCLLPLBR
  • O=C7N2c1ccccc1[C@@]64[C@@H]2[C@@H]3[C@@H](OC/C=C5\[C@@H]3C[C@@H]6N(CC4)C5)C7
Properties
C21H22N2O2
Molar mass 334.419 g·mol−1
Appearance White or translucent crystal or crystalline powder; Bitter tasting
Odor Odorless
Density 1.36 g cm−3
Melting point 270 °C; 518 °F; 543 K
Boiling point 284 to 286 °C; 543 to 547 °F; 557 to 559 K
0.02% (20°C)[2]
Acidity (pKa) 8.25[3]
Pharmacology
Legal status
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Extremely toxic
GHS labelling:
GHS06: ToxicGHS09: Environmental hazard
Danger
H300, H310, H330, H410
P260, P264, P273, P280, P284, P301+P310
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
4
0
0
Flash point Non flammable
Non flammable
Lethal dose or concentration (LD, LC):
  • 0.5 mg/kg (dog, oral)
  • 0.5 mg/kg (cat, oral)
  • 2 mg/kg (mouse, oral)
  • 16 mg/kg (rat, oral)
  • 2.35 mg/kg (rat, oral)[5]
0.6 mg/kg (rabbit, oral)[5]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 0.15 mg/m3[2]
REL (Recommended)
 TWA 0.15 mg/m3[2]
IDLH
(Immediate danger)
 3 mg/m3[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Strychnine (/ˈstrɪkniːn, -nɪn/, STRIK-neen, -⁠nin, US chiefly /-naɪn/ -⁠nyne)[6][7] is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eyes or mouth, causes poisoning which results in muscular convulsions and eventually death through asphyxia.[8] While it is no longer used medicinally, it was used historically in small doses to strengthen muscle contractions, such as a heart and bowel stimulant[9] and performance-enhancing drug. The most common source is from the seeds of the Strychnos nux-vomica tree.

Biosynthesis

Strychnine biosynthesis
Strychnine biosynthesis

Strychnine is a

Pictet-Spengler reaction to form strictosidine.[13] Many steps have been inferred by isolation of intermediates from Strychnos nux-vomica.[14] The next step is hydrolysis of the acetal, which opens the ring by elimination of glucose (O-Glu) and provides a reactive aldehyde. The nascent aldehyde is then attacked by a secondary amine to afford geissoschizine, a common intermediate of many related compounds in the Strychnos family.[10]

A reverse Pictet-Spengler reaction cleaves the C2–C3 bond, while subsequently forming the C3–C7 bond via a 1,2-alkyl migration, an oxidation from a

NADPH and hydroxylation provides the Wieland-Gumlich aldehyde, which was first isolated by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich in 1932.[14][16] To elongate the appendage by two carbons, acetyl-CoA is added to the aldehyde in an aldol reaction to afford prestrychnine. Strychnine is then formed by a facile addition of the amine with the carboxylic acid or its activated CoA thioester
, followed by ring-closure via displacement of an activated alcohol.

Chemical synthesis

Main article: Strychnine total synthesis

As early researchers noted, the strychnine molecular structure, with its specific array of

Sir Robert Robinson).[18][19]

The first total synthesis of strychnine was reported by the research group of R. B. Woodward in 1954, and is considered a classic in this field.[20][10] The Woodward account published in 1954 was very brief (3 pages),[21] but was followed by a 42-page report in 1963.[22] The molecule has since received continuing wide attention in the years since for the challenges to synthetic organic strategy and tactics presented by its complexity; its synthesis has been targeted and its stereocontrolled preparation independently achieved by more than a dozen research groups since the first success.

Mechanism of action

Strychnine is a

Aplysia californica acetylcholine binding protein (a homolog of nicotinic receptors) with high affinity but low specificity, and does so in multiple conformations.[24]

Toxicity

Main article: Strychnine poisoning

In high doses, strychnine is very toxic to humans (minimum lethal oral dose in adults is 30–120 mg) and many other animals (oral

pericarp is quite hard and indigestible; poisoning symptoms may therefore not appear if the seeds are ingested whole.[26][27]

Animal toxicity

Abruzzo National Park
, Italy, 1924.

Strychnine poisoning in animals usually occurs from ingestion of baits designed for use against gophers, moles, and coyotes. Strychnine is also used as a

fruit bats. The drugstore beetle
has a symbiotic gut yeast that allows it to digest pure strychnine.

Strychnine toxicity in rats is dependent on sex. It is more toxic to females than to males when administered via

convulsions. Death occurs as a result of respiratory arrest. The clinical signs of strychnine poisoning relate to its effects on the central nervous system. The first clinical signs of poisoning include nervousness, restlessness, twitching of the muscles, and stiffness of the neck. As the poisoning progresses, the muscular twitching becomes more pronounced and convulsions suddenly appear in all the skeletal muscles. The limbs are extended and the neck is curved to opisthotonus
. The pupils are widely dilated. As death approaches, the convulsions follow one another with increased rapidity, severity, and duration. Death results from asphyxia due to prolonged paralysis of the respiratory muscles. Following the ingestion of strychnine, symptoms of poisoning usually appear within 15 to 60 minutes.

The LD50 values for strychnine in animals
Organism Route LD50 (mg/kg) Ref.
Bird (wild) Oral 16 [29]
Cat Intravenous 0.33 [30]
Cat Oral 0.5 [31]
Dog Intravenous 0.8 [32]
Dog Subcutaneous 0.35 [30]
Dog Oral 0.5 [31]
Duck Oral 3.0 [29]
Mouse Intraperitoneal 0.98 [33]
Mouse Intravenous 0.41 [34]
Mouse Oral 2.0 [35]
Mouse Parenteral 1.06 [36]
Mouse Subcutaneous 0.47 [37]
Pigeon Oral 21.0 [29]
Quail Oral 23.0 [29]
Rabbit Intravenous 0.4 [32]
Rabbit Oral 0.6 [30]
Rat Oral 16.0 [38]
Rat Intravenous 2.35 [39]

Human toxicity

An 1809 painting by Charles Bell depicting opisthotonus caused by tetanus

After injection, inhalation, or ingestion, the first symptoms to appear are generalized

stiffness,[40] hypervigilance, and agitation.[41] Seizures caused by strychnine poisoning can start as early as 15 minutes after exposure and last 12–24 hours. They are often triggered by sights, sounds, or touch and can cause other adverse symptoms, including hyperthermia, rhabdomyolysis, myoglobinuric kidney failure, metabolic acidosis, and respiratory acidosis. During seizures, mydriasis (abnormal dilation), exophthalmos (protrusion of the eyes), and nystagmus (involuntary eye movements) may occur.[28]

As strychnine poisoning progresses,

water-electrolyte imbalance, leukocytosis (high number of white blood cells), trismus (lockjaw), risus sardonicus (spasm of the facial muscles), and opisthotonus (dramatic spasm of the back muscles, causing arching of the back and neck) can occur. In rare cases, the affected person may experience nausea or vomiting.[28]

The proximate cause of death in strychnine poisoning can be

multiple organ failure, or brain damage.[28]

Minimum lethal dose estimates for strychnine in humans
Type Route Dose (mg) Ref.
Human Oral 100–120 [42][43]
Human Oral 30–60 [44]
Human (child) Oral 15 [45][46]
Human (adult) Oral 50–100 [47]
Human (adult) Oral 30–100 [46]
Human Intravenous 5–10 (approximate) [48]

For occupational exposures to strychnine, the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health have set exposure limits at 0.15 mg/m3 over an 8-hour work day.[2]

Because strychnine produces some of the most dramatic and painful symptoms of any known toxic reaction, strychnine poisoning is often portrayed in literature and film including authors Agatha Christie and Arthur Conan Doyle.[49]

Pharmacokinetics

Absorption

Strychnine may be introduced into the body orally, by inhalation, or by injection. It is a potently bitter substance, and in humans has been shown to activate bitter taste receptors TAS2R10 and TAS2R46.[50][51][52] Strychnine is rapidly absorbed from the gastrointestinal tract.[53]

Distribution

Strychnine is transported by plasma and red blood cells. Due to slight protein binding, strychnine leaves the bloodstream quickly and distributes to bodily tissues. Approximately 50% of the ingested dose can enter the tissues in 5 minutes. Also within a few minutes of ingestion, strychnine can be detected in the urine. Little difference was noted between oral and intramuscular administration of strychnine in a 4 mg dose.[54] In persons killed by strychnine, the highest concentrations are found in the blood, liver, kidney and stomach wall. The usual fatal dose is 60–100 mg strychnine and is fatal after a period of 1–2 hours, though lethal doses vary depending on the individual.

Metabolism

Strychnine is rapidly metabolized by the liver microsomal enzyme system requiring

NADPH and O2. Strychnine competes with the inhibitory neurotransmitter glycine resulting in an excitatory state. However, the toxicokinetics after overdose have not been well described. In most severe cases of strychnine poisoning, the patient dies before reaching the hospital. The biological half-life
of strychnine is about 10 hours.

Excretion

A few minutes after ingestion, strychnine is excreted unchanged in the urine, and accounts for about 5 to 15% of a sublethal dose given over 6 hours. Approximately 10 to 20% of the dose will be excreted unchanged in the urine in the first 24 hours. The percentage excreted decreases with the increasing dose. Of the amount excreted by the kidneys, about 70% is excreted in the first 6 hours, and almost 90% in the first 24 hours. Excretion is virtually complete in 48 to 72 hours.[55]

Treatment

There is no specific

anticonvulsants such as phenobarbital or diazepam,[28] along with muscle relaxants such as dantrolene to combat muscle rigidity. Historically chloroform or heavy doses of chloral, bromide, urethane or amyl nitrite were used to restrain the convulsions.[64][65][66][67] Because medications such as diazepam are not effective to relieve convulsions in all cases, concurrent use of barbiturates and/or propofol can be utilized.[68]

The sine qua non of strychnine toxicity is the "awake" seizure, in which tonic-clonic activity occurs but the patient is alert and oriented throughout and afterwards.[69] Accordingly, George Harley (1829–1896) showed in 1850 that curare (wourali) was effective for the treatment of tetanus and strychnine poisoning.

History

Strychnine was the first alkaloid to be identified in plants of the genus Strychnos, family Loganiaceae. Strychnos, named by Carl Linnaeus in 1753, is a genus of trees and climbing shrubs of the Gentianales order. The genus contains 196 various species and is distributed throughout the warm regions of Asia (58 species), America (64 species), and Africa (75 species). The seeds and bark of many plants in this genus contain strychnine.

The toxic and medicinal effects of

predators
. Strychnos ignatii is a woody climbing shrub of the Philippines. The fruit of the plant, known as Saint Ignatius' bean, contains as many as 25 seeds embedded in the pulp. The seeds contain more strychnine than other commercial alkaloids. The properties of S. nux-vomica and S. ignatii are substantially those of the alkaloid strychnine.

Strychnine was first discovered by French chemists

Pierre-Joseph Pelletier in 1818 in the Saint-Ignatius' bean.[70][71] In some Strychnos plants a 9,10-dimethoxy derivative of strychnine, the alkaloid brucine, is also present. Brucine is not as poisonous as strychnine. Historic records indicate that preparations containing strychnine (presumably) had been used to kill dogs, cats, and birds in Europe as far back as 1640.[55] It was allegedly used by convicted murderer William Palmer to kill his final victim, John Cook.[72] It was also used during World War II by the Dirlewanger Brigade against civilian population.[73]

The structure of strychnine was first determined in 1946 by Sir

Robert Robinson and in 1954 this alkaloid was synthesized in a laboratory by Robert B. Woodward. This is one of the most famous syntheses in the history of organic chemistry. Both chemists won the Nobel prize (Robinson in 1947 and Woodward in 1965).[55]

Strychnine has been used as a plot device in the author Agatha Christie's murder mysteries.[74]

Performance enhancer

Strychnine was popularly used as an athletic performance enhancer and recreational stimulant in the late 19th century and early 20th century, due to its convulsant effects. One notorious instance of its use was during the 1904 Olympics marathon, when track-and-field athlete Thomas Hicks was unwillingly administered a concoction of egg whites and brandy laced with a small amount of strychnine by his assistants to boost his stamina. Hicks won the race, but was hallucinating[75] by the time he reached the finish line, and soon after collapsed.[76] Maximilian Theodor Buch proposed it as a cure for alcoholism around the same time. It was thought to be similar to coffee.[77][78] Its effects are well-described in H. G. Wells's novella The Invisible Man: the title character states "Strychnine is a grand tonic ... to take the flabbiness out of a man." Dr Kemp, an acquaintance, replies: "It's the devil. It's the palaeolithic in a bottle."[79]

See also

References

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