Toxiferine

Toxiferine, also known as c-toxiferine I, is a potent alkaloid toxin derived from several plant species, including Strychnos toxifera and Chondrodendron tomentosum. Historically, it has been used as an arrow poison by indigenous peoples in South America for its neuromuscular blocking properties, allowing them to paralyze animals during hunting. Toxiferine is the most important component in calabash curare, a poison traditionally prepared using hollow gourds. The preparation of curare poisons involves complex rituals where the tribes extract toxins from various plants.

Toxiferine
Clinical data
Other namesC-Toxiferine I

C-Toxiferin I

Toxiferine I
Identifiers
  • (2E)-2-[(1S,9Z,11S,13S,14S,17S,25Z,27S,30S,33S,35S,36S,38E)-38-(2-hydroxyethylidene)-14,30-dimethyl-8,24-diaza-14,30-diazoniaundecacyclo[25.5.2.211,14.11,26.110,17.02,7.013,17.018,23.030,33.08,35.024,36]octatriaconta-2,4,6,9,18,20,22,25-octaen-28-ylidene]ethanol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC40H46N4O2
Molar mass614.834 g·mol−1
3D model (JSmol)
  • [H][C@@]12[C@@]3(CC[N+]2(C)C/C4=C/CO)[C@@]5([H])N(C6=C3C=CC=C6)/C=C7[C@]([C@@]8(CC[N+]9(C)C/%10)[C@]9([H])C[C@]\7([H])C%10=C/CO)([H])N(C%11=C8C=CC=C%11)/C=C5/[C@]4([H])C1
  • InChI=1S/C40H46N4O2/c1-43-15-13-39-31-7-3-5-9-33(31)41-22-30-28-20-36-40(14-16-44(36,2)24-26(28)12-18-46)32-8-4-6-10-34(32)42(38(30)40)21-29(37(39)41)27(19-35(39)43)25(23-43)11-17-45/h3-12,21-22,27-28,35-38,45-46H,13-20,23-24H2,1-2H3/q+2/b25-11-,26-12-,29-21-,30-22-/t27-,28-,35-,36-,37-,38-,39+,40+,43-,44-/m0/s1

Originally, toxiferine was used to make poisoned arrows. The poisonous mixture also contained other curares. These poisoned arrows were used to hunt for animals as the poison can paralyze the muscles of organisms if it enters the bloodstream. It can also even kill organisms due to paralysis of the respiratory muscles.[1] The paralysis caused by toxiferine is very similar to d-tubocurarine, however toxiferine is ~170 times as potent.[2]

It is a nicotinic acetylcholine receptor antagonist. This alkaloid is the main toxic component of Calabash curare, and one of the most toxic plant alkaloids known. The lethal dose (LD50) for mice has been determined as 10 - 60 μg/kg by intravenous administration.[3] It is a muscle relaxant that causes paralysis of skeletal muscle, which takes approximately 2 hours to recovery for a moderate dose, and 8 hours of total paralysis with a 20-fold paralytic dose. The paralysis can be antagonized by neostigmine.[4]

History

Curare was discovered in 1595, however toxiferine was only first isolated and characterized in 1941 by Wieland, Bähr and Witkop.[5] They managed to produce only a couple micrograms of this compound as it is quite hard to isolate in large enough quantities to study. This is due to the complexity of curare as it is composed of many different alkaloids. In 1949 King was able to isolate 12 different types of toxiferines (I to XII).[6] In 1951 some of these toxiferine types were analyzed for their toxicological and pharmacological properties. These types were found to differ slightly in structure and their potency.[2]

Curares like tubocurarine were later used as anesthetics in medical procedures, but were replaced in the 1960s by synthetic curare-like drugs like alcuronium, pancuronium, atracurium and vecuronium. These drugs were safer to use as they had a shorter duration of action and less side effects.[7]

After the replacement of curares by these synthetic alternatives, research on toxiferine declined as it was hard to isolate from calabash curare and better alternatives to curares had been found thus decreasing the interest in researching this specific compound. However, curares as a whole have been (and still are) extensively researched.[7]

Mechanism of action

Toxiferine I competes with acetylcholine, a neurotransmitter, for binding to the nicotinic acetylcholine receptors on the post-synaptic membrane of the neuromuscular junction. By binding to these receptors, toxiferine I prevents acetylcholine from attaching to them. This inhibition blocks the ion channels associated with these receptors from opening, thereby preventing the influx of sodium ions into the muscle cell. The prevention of sodium influx leads to an inhibition of depolarization of the post-synaptic membrane, which is a necessary step for muscle contraction. Without depolarization, the muscle fiber cannot generate an action potential, resulting in muscle paralysis.

Toxiferine I is a potent blocker of several acetylcholine receptors:[8]

Affinities of toxiferine and related compounds for acetylcholine receptor subtypes
Compoundnicotinic acetylcholine receptor
(muscle-type nAChR)
Ki (nM)		alpha-7 nicotinic receptor
(α7 nAChR)
IC50 (nM)		muscarinic acetylcholine
receptor M2 (allosteric site)
EC0.5,diss (nM)
toxiferine I14950096
alcuronium23441002

Chemistry

Structure

Toxiferine I is an indole alkaloid derived from tryptamine. It has a dimeric structure with each monomer containing a quaternary ammonium salt. The parent structure, without counter ions, has the molecular formula C40H46N4O22+,[9] while the dichloride salt has the molecular formula C40H46N4O2Cl2. Alkaloids are naturally occurring compounds that are basic and contain at least one nitrogen atom.[10] Toxiferine is classified as a dimeric bisindole alkaloid because it is symmetrically constructed from two identical monomeric units, each containing an indole ring.[11][12]

Analogues

A dozen different types of toxiferine were found to exist (designated as toxiferine I to XII),[6] but the different structures of toxiferine II till XII have not been studied in great detail. Toxiferine does have multiple analogues which are researched extensively. Some of these include: bisnortoxiferine, caracurine V and alcuronium. Caracurine V is, like toxiferine, another naturally occurring curare toxin from the strychnos toxifera.[13] Caracurine V, unlike the other analogues, has a closed ring formed between the hydroxyl groups and the middle ring. Though the main difference between the analogues are the side groups attached to the positive nitrogen atom, also called the quaternary ammonium ion. The main target of toxiferine and its analogues are acetylcholine receptors. It is this quaternary ammonium ion that both toxiferine and its analogues share with acetylcholine that gives them their specific affinity for these receptors. The difference in hydroxyl side groups together with most importantly the quaternary ammonium side groups is what causes variability in receptor affinity and metabolic activity and with this a variability in the toxic properties of these analogues.[8] From this it can be concluded that the side groups of toxiferine, mainly those attached to the quaternary ammonium have large effect over its reactivity and affinity, but to this day no research exists that can reliably explain the structural reactivity of toxiferine.

Biosynthesis

Toxiferine is thought to be biosynthetically derived from the monoterpenoid indole alkaloid strictosidine. Strictosidine in turn is derived from the alkaloid tryptamine and the terpene secologanin through the action of strictosidine synthase.[14]

Toxiferine is an indole alkaloid. Indole alkaloids are the largest among the alkaloids. They are primarily synthesized using tryptophan.[15][16] The dimeric subunits of toxiferine bear high similarity to strychnine and are most likely a related product of its biosynthesis. Especially the intermediate Wieland-Gumlich aldehyde is very similar to the dimeric subunits of toxiferine, though this lacks the quaternary ammonium ion. The biosynthesis of strychnine was solved in 2022.[17] It is also possible to artificially synthesise strychnine. The exact biosynthetic and possible artificial ways to synthesise toxiferine are not known.

ADME

This describes the ADME of toxiferine.

Absorption

Toxiferine is known to enter the body in two different ways: either orally by ingestion or intravenously while applied to a sharp tip for killing purposes. When orally ingested, toxiferine is only absorbed minimally into the plasma and is not known to be dangerous even though it has a very high potency. Intravenous absorption is thus the only way of effective administration.[7]

Distribution

The distribution of toxiferine has been researched in rats. Toxiferine distributes through the body in a way that is similar to other non-depolarizing curare alkaloids. Toxiferine is a highly water soluble substance and because of this also generally not lipophilic. Toxiferine does not easily pass the blood-brain barrier. It is mostly retained in motor endplates and the sciatic nerve where it binds to specific receptors. It was also found that toxiferine is distributed to tissues with a high acidic mucopolysaccharide content like intervertebral discs and cartilage of the ribs.[18] Alkaloids are known to have affinity for such polysaccharides at acidic extracellular pH.[19]

Metabolism

Toxiferine does not have any known metabolic pathways. This may be due to its low lipophilicity. Bis-quaternary nitrogen compounds like toxiferine have shown to be dependent on their lipophilicity to be transported to sites in the liver.[20] The liver, which is the main site of metabolic activity, can thus not or hardly be reached. When comparing the metabolic activity of toxiferine to that of maybe its most important analogue alcuronium, it is observed that the allylic side chains of alcuronium make it more potent for biotransformation than toxiferine with its methyl side chains. This makes the duration of action of toxiferine significantly longer when compared to alcuronium.[21]

Excretion

Toxiferine is mainly excreted in the urine even though elimination of toxiferine by the kidney is very poor relative to its analogue alcuronium. Toxiferine has a strong receptor affinity, which together with the poor excretion makes it accumulate in the body rapidly after repeated administration.[18][22] This is another reason why toxiferine has an especially long duration of action in the body.

References
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  2. Paton WD, Perry WL (June 1951). "The pharmacology of the toxiferines". British Journal of Pharmacology and Chemotherapy. 6 (2): 299–310. doi:10.1111/j.1476-5381.1951.tb00643.x. PMC 1509221. PMID 14848460.
  3. Entry on C-Toxiferine I. at: Römpp Online. Georg Thieme Verlag, retrieved 8 June 2020.
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