Aconitine

 ( Diterpene Alkaloids ) 

Aconitine is an alkaloid toxin produced by various plant species belonging to the genus Aconitum (family Ranunculaceae), commonly known by the names wolfsbane and monkshood. Aconitine is notorious for its toxic properties.

Like many other alkaloids, the basic nitrogen atom in one of the six-membered ring structure of aconitine can easily form salts and ions, giving it affinity for both polar and lipophilicity structures (such as cell membranes and receptors) and making it possible for the molecule to pass the blood–brain barrier. The Acetoxy group at the c8 position can readily be replaced by a methoxy group, by heating aconitine in methanol, to produce a 8-deacetyl-8- O-methyl derivatives. If aconitine is heated in its dry state, it undergoes a pyrolysis to form pyroaconitine ((1α,3α,6α,14α,16β)-20-ethyl-3,13-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-15-oxoaconitan-14-yl benzoate) with the chemical formula C₃₂H₄₃NO₉.

Aconitine binds to the channel at the neurotoxin binding site 2 on the alpha subunit (the same site bound by batrachotoxin, veratridine, and grayanotoxin). This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium influx (which is 10–1000-fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage. In neurons, aconitine increases the permeability of the membrane for sodium ions, resulting in a huge sodium influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium ions increases rapidly, resulting in a potassium reflux to release the positive charge out of the cell. Not only the permeability for potassium ions but also the permeability for calcium ions increases as a result of the depolarization of the membrane. A calcium influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the Chemical synapse. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential.

Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0.1 μM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension. Action potentials are generated more often at this concentration. At higher concentration (0.3–3 μM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3 μM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.

Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory. In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its total synthesis. The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that makes up its core and the elaborate collection of oxygenated functional groups at its periphery. A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically. In 1971, the Weisner group discovered the total synthesis of talatisamine (a C19-norditerpenoid). In the subsequent years, they also discovered the Total synthesis of other C19-norditerpenoids, such as chasmanine, and 13-deoxydelphonine.

The total synthesis of napelline ( Scheme a) begins with aldehyde 100. In a 7 step process, the A-ring of napelline is formed ( 104). It takes another 10 steps to form the lactone ring in the pentacyclic structure of napelline ( 106). An additional 9 steps creates the enone-aldehyde 107. Heating in methanol with potassium hydroxide causes an aldol condensation to close the sixth and final ring in napelline ( 14). Oxidation then gives rise to diketone 108 which was converted to (±)-napelline ( 14) in 10 steps.

A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone ( Scheme c). The first step of this synthesis is the generation of a conjugated enone 112 from 111 in 4 steps. This is followed by the addition of a benzyl vinyl ether to produce 113. In 11 steps, this compound is converted to ketal 114. The addition of heat, DMSO and o-xylene rearranges this ketol ( 115), and after 5 more steps (±)-13-desoxydelphinone ( 15) is formed.

Lastly, talatisamine ( Scheme d) is synthesized from diene 116 and nitrile 117. The first step is to form tricycle 118 in 16 steps. After another 6 steps, this compound is converted to enone 120. Subsequently, this allene is added to produce Adduct 121. This adduct group is cleaved and rearrangement gives rise to the compound 122. In 7 steps, this compound forms 123, which is then rearranged, in a similar manner to compound 114, to form the aconitine-like skeleton in 124. A racemic relay synthesis is completed to produce talatisamine ( 13).

More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominine and neofinaconitine.

Selective enzyme inhibitor were used to determine the involved CYPs in the aconitine metabolism. The results indicate that aconitine was mainly metabolized by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism, whereas CYP1A2, 2E1 and 2C19 did not produce any aconitine metabolites at all. The proposed metabolic pathways of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above.

values for mice are 1 mg/kg orally, 0.100 mg/kg intravenously, 0.270 mg/kg intraperitoneally and 0.270 mg/kg subcutaneously. The lowest published lethal dose (LDLo) for mice is 1 mg/kg orally and 0.100 mg/kg intraperitoneally. The lowest published toxic dose (TDLo) for mice is 0.0549 mg/kg subcutaneously. LD50 value for rats is 0.064 mg/kg intravenously. The LDLo for rats is 0.040 mg/kg intravenously and 0.250 mg/kg intraperitoneally. The TDLo for rats is 0.040 mg/kg parenterally. For an overview of more test animal results (LD50, LDLo and TDLo) see the following table.
     

Rufus T. Bush, American industrialist and yachtsman, died on September 15, 1890, after accidentally taking a fatal dose of aconite.

In 1953 aconitine was used by a Soviet biochemist and poison developer, Grigory Mairanovsky, in experiments with prisoners in the secret NKVD laboratory in Moscow. He admitted killing around 10 people using the poison.

In 2004 Canadian actor Andre Noble died from aconitine poisoning. He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland.

In 2009 Lakhvir Singh of Feltham, west London, used aconitine to poison the food of her ex-lover Lakhvinder Cheema (who died as a result of the poisoning) and his current fiancée Gurjeet Choongh. Singh received a life sentence with a 23-year minimum for the murder on February 10, 2010.

In 2022, twelve diners at a restaurant in York Region became acutely ill following a meal. All twelve became seriously ill and four of them were admitted to the intensive care unit after the suspected poisoning.

Lurida terribiles miscent aconita novercae.Ovid, Metamorphoses, 1.147

Fearsome stepmothers mix lurid aconites.

Aconitine was also made famous by its use in Oscar Wilde's 1891 story "Lord Arthur Savile's Crime". Aconite also plays a prominent role in James Joyce's Ulysses, in which the father to protagonist Leopold Bloom used pastilles of the chemical to commit suicide. Aconitine poisoning plays a key role in the murder mystery Breakdown by Jonathan Kellerman (2016). In Twin Peaks season 3 part 13, aconitine is suggested as a means to poison the main character.

Monk's Hood is the name of the third Cadfael novel written in 1980 by Ellis Peters. The novel was made into an episode of the television series Cadfael starring Derek Jacobi.

In the third season of the Netflix series You, two of the main characters poison each other with aconitine. One survives (due to a lower dose and an antidote), and the other is killed.

Hannah McKay (Yvonne Strahovski), a serial killer in the Showtime series Dexter uses aconite on at least three occasions to poison her victims.

In season 2 episode 16 of the series Person Of Interest, aconitine is shown in a syringe stuck to the character Shaw (Sarah Shahi) nearly being injected and causing her death, until she is rescued by Reese (Jim Caviezel).

In a 2017 episode of The Doctor Blake Mysteries, fight manager Gus Jansons (Steve Adams) murdered his boxer, Mickey Ellis (Trey Coward), during a match by applying aconitine he had put in petroleum jelly and applying it to a cut over the boxer’s eye. He feared being over a murder he helped cover up. He had made the poison from Aconitum he had seen in a local garden.December Media Pty. “A Lethal Combination.” The Doctor Blake Mysteries, Season 5, Episode 1. Australian Broadcasting Corporation, 17 September 2017.

Aconitine poisoning is used by Villanelle to kill the Ukrainian gangster, Rinat Yevtukh in Killing Eve: No Tomorrow by Luke Jennings (2018).

• Pseudaconitine
• Tetrodotoxin, a sodium channel blocker