Resiniferatoxin (RTX) is a naturally occurring chemical found in resin spurge ('' Euphorbia resinifera''), a cactus-like plant commonly found in

Morocco Morocco, officially the Kingdom of Morocco, is a country in the Maghreb region of North Africa. It has coastlines on the Mediterranean Sea to the north and the Atlantic Ocean to the west, and has land borders with Algeria to Algeria–Morocc ...

, and in '' Euphorbia poissonii'' found in northern

Nigeria Nigeria, officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf of Guinea in the Atlantic Ocean to the south. It covers an area of . With Demographics of Nigeria, ...

.''Euphorbia poissonii''
in BoDD – Botanical Dermatology Database It is a potent functional analog of

capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) (, rarely ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a potent Irritation, irritant for Mammal, mammals, including humans, and produces ...

, the active ingredient in

chili peppers Chili peppers, also spelled chile or chilli ( ), are varieties of berry-fruit plants from the genus ''Capsicum'', which are members of the nightshade family Solanaceae, cultivated for their pungency. They are used as a spice to add pungency ( ...

Biological activity

Resiniferatoxin has a score of 16 billion Scoville heat units, making pure resiniferatoxin about 500 to 1000 times hotter than pure

. Resiniferatoxin activates transient vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in

nociception In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...

, the transmission of

physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

pain. TRPV1 is an ion channel in the plasma membrane of sensory neurons and stimulation by resiniferatoxin causes this ion channel to become permeable to

cations An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

, especially

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

. The influx of cations causes the neuron to depolarize, transmitting signals similar to those that would be transmitted if the innervated tissue were being burned or damaged. This stimulation is followed by desensitization and

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

, in part because the nerve endings die from calcium overload.

Total synthesis

total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...

of (+)-resiniferatoxin was completed by the Paul Wender group at

Stanford University Leland Stanford Junior University, commonly referred to as Stanford University, is a Private university, private research university in Stanford, California, United States. It was founded in 1885 by railroad magnate Leland Stanford (the eighth ...

in 1997. The process begins with a starting material of 1,4-pentadien-3-ol and consists of more than 25 significant steps. As of 2007, this represented the only complete total synthesis of any member of the daphnane family of molecules. One of the main challenges in synthesizing a molecule such as resiniferatoxin is forming the three-ring backbone of the structure. The Wender group was able to form the first ring of the structure by first synthesizing Structure 1 in Figure 1. By reducing the ketone of Structure 1 followed by oxidizing the furan nucleus with m-CPBA and converting the resulting hydroxy group to an oxyacetate, Structure 2 can be obtained. Structure 2 contains the first ring of the three-ring structure of RTX. It reacts through an oxidopyrylium cycloaddition when heated with DBU in

acetonitrile Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not class ...

to form Structure 4 by way of Intermediate 3. Several steps of synthesis are required to form Structure 5 from Structure 4, with the main goal of positioning the

allylic In organic chemistry, an allyl group is a substituent with the structural formula . It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, . In 1844, Theodor Wertheim isolat ...

branch of the seven-membered ring in a ''trans'' conformation. Once this conformation is achieved, zirconocene-mediated cyclization of Structure 5 can occur, and oxidizing the resulting hydroxy group with TPAP will yield Structure 6. Structure 6 contains all three rings of the RTX backbone and can then be converted to resiniferatoxin through additional synthesis steps attaching the required functional groups. An alternative approach to synthesizing the three-ring backbone makes use of radical reactions to create the first and third rings in a single step, followed by the creation of the remaining ring. It has been proposed by the Masayuki Inoue group of the

University of Tokyo The University of Tokyo (, abbreviated as in Japanese and UTokyo in English) is a public research university in Bunkyō, Tokyo, Japan. Founded in 1877 as the nation's first modern university by the merger of several pre-westernisation era ins ...

Toxicity

At 16 billion Scoville units, resiniferatoxin is rather toxic and can inflict

chemical burn A chemical burn occurs when living tissue is exposed to a corrosive substance (such as a strong acid, base or oxidizer) or a cytotoxic agent (such as mustard gas, lewisite or arsine). Chemical burns follow standard burn classification and m ...

s in minute quantities. The primary action of resiniferatoxin is to activate sensory neurons responsible for the perception of pain. It is currently the most potent TRPV1 agonist known, with ~500x higher binding affinity for TRPV1 than pure

, the active ingredient in hot chili peppers such as those produced by ''

Capsicum annuum ''Capsicum annuum'' is a fruiting plant from the family Solanaceae (nightshades), within the genus Capsicum which is native to the northern regions of South America and to southwestern North America. The plant produces Berry, berries of many color ...

''. It is 3 to 4 orders of magnitude more potent than capsaicin for effects on thermoregulation and neurogenic inflammation. For rats,

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose requ ...

through oral ingestion is 148.1 mg/kg. It causes severe burning pain in sub-microgram (less than 1/1,000,000th of a gram) quantities when ingested orally.

Research

Sorrento Therapeutics has been developing RTX as a means to provide pain relief for forms of advanced

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. The nerve desensitizing properties of RTX were once thought to be useful to treat

overactive bladder Overactive bladder (OAB) is a common condition where there is a frequent feeling of needing to urinate to a degree that it negatively affects a person's life. The frequent need to urinate may occur during the day, at night, or both. Loss of bl ...

(OAB) by preventing the bladder from transmitting "sensations of urgency" to the brain, similar to how they can prevent nerves from transmitting signals of pain; RTX has never received

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approval for this use. RTX has also previously been investigated as a treatment for

interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the Urinary bladder, bladder and pelvic floor of unknown cause. Symptoms include urinary urgency, feeling the need to urinate right away, urinary frequency, ...

rhinitis Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip. The inflammation is caused by viruses, bacteria, irritant ...

, and lifelong

premature ejaculation Premature ejaculation (PE) is a male sexual dysfunction that occurs when a male Ejaculation, expels semen (and most likely experiences orgasm) soon after beginning sexual activity, and with minimal penile stimulation. It has also been called ''e ...

(PE).

References

External links

"Fiery Pepper May Hold Key to Easing Pain"
Lauran Neergaard,

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