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 | |
| 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 |
| KEGG |
|
| RTECS number |
|
| UNII |
|
| UN number | 1692 |
| |
| |
| 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: | |
  | |
| Danger | |
| H300,H310,H330,H410 | |
| P260,P264,P273,P280,P284,P301+P310 | |
| NFPA 704 (fire diamond) | |
| Flash point | Non flammable |
| Non flammable | |
| Lethal dose or concentration (LD, LC): | |
LD50 (median dose) |
|
LDLo (lowest published) | 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 theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Strychnine (/ˈstrɪkniːn,-nɪn/,STRIK-neen, -nin,US chiefly/-naɪn/-nyne)[6][7] is a highlytoxic, colorless, bitter,crystallinealkaloid used as apesticide, particularly for killing smallvertebrates such asbirds androdents. Strychnine, when inhaled, swallowed, or absorbed through the eyes or mouth, causespoisoning which results in muscularconvulsions and eventually death throughasphyxia.[8] While it is no longer used medicinally, it was used historically in small doses to strengthen muscle contractions, such as a heart[9] and bowel stimulant[10] and performance-enhancing drug. The most common source is from the seeds of theStrychnos nux-vomica tree.
Strychnine is aterpeneindolealkaloid belonging to theStrychnos family ofCorynanthe alkaloids, and it is derived fromtryptamine andsecologanin.[11][12] The biosynthesis of strychnine was solved in 2022.[13] The enzyme,strictosidine synthase, catalyzes the condensation of tryptamine and secologanin, followed by aPictet-Spengler reaction to formstrictosidine.[14] Many steps have been inferred by isolation of intermediates fromStrychnos nux-vomica.[15] The next step is hydrolysis of theacetal, which opens the ring by elimination ofglucose (O-Glu) and provides a reactive aldehyde. The nascent aldehyde is then attacked by a secondary amine to affordgeissoschizine, a common intermediate of many related compounds in theStrychnos family.[11]
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 aCytochrome P450 enzyme to a spiro-oxindole, nucleophilic attack from theenol at C16, and elimination of oxygen forms the C2–C16 bond to providedehydropreakuammicine.[16] Hydrolysis of the methyl ester anddecarboxylation leads tonorfluorocurarine. Stereospecific reduction of the endocyclic double bond byNADPH andhydroxylation provides theWieland-Gumlich aldehyde, which was first isolated by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich in 1932.[15][17] To elongate the appendage by two carbons,acetyl-CoA is added to the aldehyde in analdol reaction to afford prestrychnine. Strychnine is then formed by a facile addition of the amine with thecarboxylic acid or its activated CoAthioester, followed by ring-closure via displacement of an activated alcohol.
As early researchers noted, the strychnine molecular structure, with its specific array ofrings,stereocenters, and nitrogenfunctional groups, is a complex synthetic target, and has stimulated interest for that reason and for interest in thestructure–activity relationships underlying its pharmacologic activities.[18] An early synthetic chemist targeting strychnine,Robert Burns Woodward, quoted the chemist who determined its structure through chemical decomposition and related physical studies as saying that "for its molecular size it is the most complex organic substance known" (attributed toSir Robert Robinson).[19][20]
The firsttotal synthesis of strychnine was reported by the research group of R. B. Woodward in 1954, and is considered a classic in this field.[21][11] The Woodward account published in 1954 was very brief (3 pages),[22] but was followed by a 42-page report in 1963.[23] 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.[24][25]
Strychnine is aneurotoxin which acts as anantagonist ofglycine andacetylcholine receptors. It primarily affects the motor nerve fibers in the spinal cord which control muscle contraction. An impulse is triggered at one end of a nerve cell by the binding ofneurotransmitters to the receptors. In the presence of an inhibitory neurotransmitter, such asglycine, a greater quantity of excitatory neurotransmitters must bind to receptors before anaction potential is generated. Glycine acts primarily as an agonist of the glycine receptor, which is aligand-gated chloride channel in neurons located in the spinal cord and in the brain. Thischloride channel allows the negatively charged chloride ions into the neuron, causing ahyperpolarization which pushes the membrane potential further from threshold. Strychnine is an antagonist of glycine; it binds noncovalently to the same receptor, preventing the inhibitory effects of glycine on the postsynaptic neuron. Therefore, action potentials are triggered with lower levels of excitatory neurotransmitters. When the inhibitory signals are prevented, the motor neurons are more easily activated and the victim has spastic muscle contractions, resulting in death by asphyxiation.[8][26] Strychnine binds theAplysia californica acetylcholine binding protein (a homolog ofnicotinic receptors) with high affinity but low specificity, and does so in multiple conformations.[27]
In high doses, strychnine is very toxic to humans (minimum lethal oral dose in adults is 30–120 mg) and many other animals (oralLD50 = 16 mg/kg in rats, 2 mg/kg in mice),[28] and poisoning by inhalation, swallowing, or absorption through eyes or mouth can be fatal.S. nux-vomica seeds are generally effective as a poison only when they are crushed or chewed before swallowing because thepericarp is quite hard and indigestible; poisoning symptoms may therefore not appear if the seeds are ingested whole.[29][30]
Strychnine poisoning in animals usually occurs from ingestion of baits designed for use against gophers, rats, squirrels, moles, chipmunks and coyotes. Strychnine is also used as arodenticide, but is not specific to such unwanted pests and may kill other small animals.[31][32] In the United States, most baits containing strychnine have been replaced withzinc phosphide baits since 1990. In the European Union, rodenticides with strychnine have been forbidden since 2006. Some animals are immune to strychnine; usually these have evolved resistance to poisonousstrychnos alkaloids in the fruit they eat, such asfruit bats. Thedrugstore 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 viasubcutaneous injection orintraperitoneal injection. Differences are due to higher rates of metabolism by male rat liver microsomes. Dogs and cats are more susceptible among domestic animals, pigs are believed to be as susceptible as dogs, and horses are able to tolerate relatively large amounts of strychnine. Birds affected by strychnine poisoning exhibit wing droop,salivation,tremors, muscle tenseness, andconvulsions. Death occurs as a result ofrespiratory arrest. The clinical signs of strychnine poisoning relate to its effects on thecentral 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 toopisthotonus. 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.
| Organism | Route | LD50 (mg/kg) | Ref. |
|---|---|---|---|
| Bird (wild) | Oral | 16 | [33] |
| Cat | Intravenous | 0.33 | [34] |
| Cat | Oral | 0.5 | [35] |
| Dog | Intravenous | 0.8 | [36] |
| Dog | Subcutaneous | 0.35 | [34] |
| Dog | Oral | 0.5 | [35] |
| Duck | Oral | 3.0 | [33] |
| Mouse | Intraperitoneal | 0.98 | [37] |
| Mouse | Intravenous | 0.41 | [38] |
| Mouse | Oral | 2.0 | [39] |
| Mouse | Parenteral | 1.06 | [40] |
| Mouse | Subcutaneous | 0.47 | [41] |
| Pigeon | Oral | 21.0 | [33] |
| Quail | Oral | 23.0 | [33] |
| Rabbit | Intravenous | 0.4 | [36] |
| Rabbit | Oral | 0.6 | [34] |
| Rat | Oral | 16.0 | [42] |
| Rat | Intravenous | 2.35 | [43] |
After injection, inhalation, or ingestion, the first symptoms to appear are generalizedmuscle spasms. They appear very quickly after inhalation or injection – within as few as five minutes – and take somewhat longer to manifest after ingestion, typically approximately 15 minutes. With a very high dose, the onset ofrespiratory failure andbrain death can occur in 15 to 30 minutes. If a lower dose is ingested, other symptoms begin to develop, includingseizures, cramping,stiffness,[44]hypervigilance, andagitation.[45] 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, includinghyperthermia,rhabdomyolysis, myoglobinurickidney failure,metabolic acidosis, andrespiratory acidosis. During seizures,mydriasis (abnormal dilation),exophthalmos (protrusion of the eyes), andnystagmus (involuntary eye movements) may occur.[32]
As strychnine poisoning progresses,tachycardia (rapid heart beat),hypertension (high blood pressure),tachypnea (rapid breathing),cyanosis (blue discoloration),diaphoresis (sweating),water-electrolyte imbalance,leukocytosis (high number ofwhite blood cells),trismus (lockjaw),risus sardonicus (spasm of the facial muscles), andopisthotonus (dramatic spasm of the back muscles, causing arching of the back and neck) can occur. In rare cases, the affected person may experiencenausea orvomiting.[32]
The proximate cause of death in strychnine poisoning can becardiac arrest,respiratory failure,multiple organ failure, orbrain damage.[32]
| Type | Route | Dose (mg) | Ref. |
|---|---|---|---|
| Human | Oral | 100–120 | [46][47] |
| Human | Oral | 30–60 | [48] |
| Human (child) | Oral | 15 | [49][50] |
| Human (adult) | Oral | 50–100 | [51] |
| Human (adult) | Oral | 30–100 | [50] |
| Human | Intravenous | 5–10 (approximate) | [52] |
For occupational exposures to strychnine, theOccupational Safety and Health Administration and theNational 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 authorsAgatha Christie andArthur Conan Doyle.[53]
There is noantidote for strychnine poisoning.[54] Strychnine poisoning demands aggressive management with early control of muscle spasms, intubation for loss of airway control, toxin removal (decontamination), intravenous hydration and potentially active cooling efforts in the context of hyperthermia as well ashemodialysis in kidney failure (strychnine has not been shown to be removed by hemodialysis).[55] Treatment involves oral administration ofactivated charcoal, whichadsorbs strychnine within the digestive tract; unabsorbed strychnine is removed from the stomach bygastric lavage, along withtannic acid orpotassium permanganate solutions to oxidize strychnine.[56]
Activated charcoal is a substance that can bind to certain toxins in the digestive tract and prevent their absorption into the bloodstream.[57] The effectiveness of this treatment, as well as how long it is effective after ingestion, are subject to debate.[58][59][60] According to one source, activated charcoal is only effective within one hour of poison being ingested, although the source does not regard strychnine specifically.[61] Other sources specific to strychnine state that activated charcoal may be used after one hour of ingestion, depending on dose and type of strychnine-containing product.[62][59] Therefore, other treatment options are generally favoured over activated charcoal.[59][63]
The use of activated charcoal is considered dangerous in patients with tenuous airways or altered mental states.[64]
Most other treatment options focus on controlling the convulsions that arise from strychnine poisoning. These treatments involve keeping the patient in a quiet and darkened room,[65]anticonvulsants such asphenobarbital ordiazepam,[55] muscle relaxants such asdantrolene,[66] barbiturates andpropofol,[67] andchloroform or heavy doses ofchloral,bromide,urethane oramyl nitrite.[68][69][70][71] If a poisoned person is able to survive for 6 to 12 hours subsequent to initial dose, they have a good prognosis.[55]
Thesine 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.[72] Accordingly,George Harley (1829–1896) showed in 1850 thatcurare (wourali) waseffective for the treatment of tetanus and strychnine poisoning.
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 activatebitter taste receptorsTAS2R10 andTAS2R46.[73][74][75] Strychnine is rapidly absorbed from the gastrointestinal tract.[76]
Strychnine is transported byplasma andred blood cells. Due to slightprotein 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.[77] 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.
Strychnine is rapidly metabolized by the liver microsomal enzyme system requiringNADPH and O2. Strychnine competes with the inhibitoryneurotransmitterglycine resulting in an excitatory state. However, thetoxicokinetics after overdose have not been well described. In most severe cases of strychnine poisoning, the patient dies before reaching the hospital. Thebiological half-life of strychnine is about 10 hours.
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.[78]
Strychnine was the first alkaloid to be identified in plants of the genusStrychnos, familyLoganiaceae.Strychnos, named byCarl Linnaeus in 1753, is agenus of trees and climbingshrubs of theGentianales 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 ofStrychnos nux-vomica have been well known from the times of ancient India, although the chemical compound itself was not identified and characterized until the 19th century. The inhabitants of these countries had historical knowledge of the speciesStrychnos nux-vomica and Saint-Ignatius' bean (Strychnos ignatii).Strychnos nux-vomica is a tree native to thetropical forests on theMalabar Coast in Southern India, Sri Lanka and Indonesia, which attains a height of about 12 metres (39 ft). The tree has a crooked, short, thick trunk and the wood is close grained and very durable. The fruit has an orange color and is about the size of a large apple with a hardrind and contains five seeds, which are covered with a soft wool-like substance. The ripe seeds look like flattened disks, which are very hard. These seeds are the chief commercial source of strychnine and were first imported to and marketed in Europe as a poison to kill rodents and smallpredators.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 ofS. nux-vomica andS. ignatii are substantially those of the alkaloid strychnine.
Strychnine was first discovered by French chemistsJoseph Bienaimé Caventou andPierre-Joseph Pelletier in 1818 in the Saint-Ignatius' bean.[79][80] In someStrychnos plants a 9,10-dimethoxy derivative of strychnine, the alkaloidbrucine, 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.[78] It was allegedly used by convicted murdererWilliam Palmer to kill his final victim, John Cook.[81] It was also used duringWorld War II by theDirlewanger Brigade against civilian population.[82]
The structure of strychnine was first determined in 1946 by SirRobert Robinson and in 1954 this alkaloid wassynthesized in a laboratory byRobert B. Woodward. This is one of the most famous syntheses in the history of organic chemistry. Both chemists won theNobel prize (Robinson in 1947 and Woodward in 1965).[78]
Strychnine has been used as a plot device in the authorAgatha Christie's murder mysteries.[83]
Strychnine was popularly used as an athleticperformance enhancer andrecreational stimulant in the late 19th century and early 20th century, due to itsconvulsant effects. One notorious instance of its use was during the1904 Olympics marathon, when track-and-field athleteThomas Hicks was unwittingly administered a concoction of egg whites and brandy laced with a small amount of strychnine by his assistants in a vain attempt to boost his stamina. Hicks won the race, but was hallucinating[84] by the time he reached the finish line, and soon after collapsed.[85]
Maximilian Theodor Buch proposed it as a cure for alcoholism around the same time. It was thought to be similar to coffee,[86][87] and also has been used and abused recreationally.[88][89]
Its effects are well-described inH. G. Wells' novellaThe 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."[90]
An attempt was made to administer a soap-and-water enema, but the sphincter was not acting. After hypodermic injection of 1/45 grain [1.44 mg] strychnine, a second attempt was made, and a good evacuation of the bowel followed, after which half a pint [284 ml] of normal saline was injected and retained. [...] We decided to adhere to the treatment already commenced – namely, periodical rectal injection of saline and withdrawals of urine by catheter, with oxygen inhalation for cyanosis, and strychnine hypodermically as the pulse weakened.
For its molecular size it is the most complex substance known.citingWoodward RB, Cava MP, Ollis WD, Hunger A, Daeniker HU, Schenker K (1963). "The Total Synthesis of Strychnine".Tetrahedron.19 (2):247–288.doi:10.1016/S0040-4020(01)98529-1.
He began hallucinating, believing that the finish line was still 20 miles away.
