Resiniferatoxin
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Resiniferatoxin (RTX) is a naturally occurring chemical found in resin spurge (''
Euphorbia resinifera ''Euphorbia resinifera'', the resin spurge, is a species of spurge native to Morocco, where it occurs on the slopes of the Atlas Mountains. The dried latex of the plant was used in ancient medicine. It contains resiniferatoxin, an extremely pote ...
''), a cactus-like plant commonly found in
Morocco Morocco (),, ) officially the Kingdom of Morocco, is the westernmost country in the Maghreb region of North Africa. It overlooks the Mediterranean Sea to the north and the Atlantic Ocean to the west, and has land borders with Algeria to ...
, and in ''
Euphorbia poissonii ''Euphorbia poissonii'', also known as ''Euphorbia poissoni'' and, incorrectly, as ''Euphorbia poisoni'', is a highly irritant and toxic succulent member of the large and varied spurge family of plants.
'' found in northern
Nigeria Nigeria ( ), , ig, Naìjíríyà, yo, Nàìjíríà, pcm, Naijá , ff, Naajeeriya, kcg, Naijeriya officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf o ...
.''Euphorbia poissonii''
in BoDD – Botanical Dermatology Database
It is a potent functional analog of
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...
, the active ingredient in
chili peppers Chili peppers (also chile, chile pepper, chilli pepper, or chilli), from Nahuatl '' chīlli'' (), are varieties of the berry-fruit of plants from the genus ''Capsicum'', which are members of the nightshade family Solanaceae, cultivated for ...
.


Biological activity

Resiniferatoxin has a score of 16 billion
Scoville heat units The Scoville scale is a measurement of the pungency (spiciness or "heat") of chili peppers, as recorded in Scoville heat units (SHU), based on the concentration of capsaicinoids, among which capsaicin is the predominant component. The scale ...
, making pure resiniferatoxin about 500 to 1000 times hotter than pure
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...
. Resiniferatoxin activates transient vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in
nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, co ...
, the transmission of
physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
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 with the 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 ...
. 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

A
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
of (+)-resiniferatoxin was completed by the Wender group at
Stanford University Stanford University, officially Leland Stanford Junior University, is a private research university in Stanford, California. The campus occupies , among the largest in the United States, and enrolls over 17,000 students. Stanford is consider ...
in 1997. The process begins with a starting material of 1,4-pentadien-3-ol and consists of more than 25 significant steps. , 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 ''meta''-Chloroperoxybenzoic acid (mCPBA or ''m''CPBA) is a peroxycarboxylic acid. A white solid, it is used widely as an oxidant in organic synthesis. mCPBA is often preferred to other peroxy acids because of its relative ease of handling. mC ...
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 The decibel (symbol: dB) is a relative unit of measurement equal to one tenth of a bel (B). It expresses the ratio of two values of a Power, root-power, and field quantities, power or root-power quantity on a logarithmic scale. Two signals whose ...
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 clas ...
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 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
Inoue Inoue (kanji: , historical kana orthography: ''Winouhe'') is the 16th most common Japanese surname. Historically, it was also romanized as Inouye, and many Japanese-descended people outside of Japan still retain this spelling. A less common vari ...
group of the
University of Tokyo , abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...
.


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 may ca ...
s in tiny 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
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...
, the active ingredient in hot chili peppers such as those produced by ''
Capsicum annuum ''Capsicum annuum'' is a species of the plant genus ''Capsicum'' native to southern North America, the Caribbean, and northern South America. This species is the most common and extensively cultivated of the five domesticated capsicums. The spec ...
''. 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 toxin, radiation, or pathogen. The value of LD50 for a substance is the ...
through oral ingestion is 148.1 mg/kg. Animal experiments on rats suggest that, in humans, ingestion of 1.672 g may be fatal or cause serious damage to health. 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 abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. The nerve desensitizing properties of RTX were once thought to be useful to treat
overactive bladder Overactive bladder (OAB) is a 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. If there is loss ...
(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 bladder and pelvic floor of unknown cause. It is the urologic chronic pelvic pain syndrome of women. Symptoms include feeling the need to urinate right awa ...
,
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, irritants o ...
, and lifelong
premature ejaculation Premature ejaculation (PE) occurs when a man expels semen (and most likely experiences orgasm) soon after beginning sexual activity, and with minimal penile stimulation. It has also been called ''early ejaculation'', ''rapid ejaculation'', ''ra ...
(PE).


See also

*
List of investigational analgesics This is a list of investigational analgesics, or analgesics that are currently under development for clinical use but are not yet approved. ''Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in pare ...
* Discovery and development of TRPV1 antagonists *
Iodoresiniferatoxin Iodoresiniferatoxin (I-RTX) is a strong competitive receptor antagonist, antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX). Sources I-RTX can be prepared from RTX by electroph ...
*
Phenylacetylrinvanil Phenylacetylrinvanil (IDN-5890) is a synthetic analogue of capsaicin which acts as a potent and selective agonist for the TRPV1 receptor, with slightly lower potency than resiniferatoxin, though still around 300 times the potency of capsaicin. It ...
*
Transient receptor potential Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TR ...
*
Tinyatoxin Tinyatoxin (TTX or TTN) is an analog of the neurotoxin resiniferatoxin. It occurs naturally in '' Euphorbia poissonii''.


References


External links


Fiery pepper may hold key to easing pain
Lauran Neergaard,
The Associated Press The Associated Press (AP) is an American non-profit news agency headquartered in New York City. Founded in 1846, it operates as a cooperative, unincorporated association. It produces news reports that are distributed to its members, U.S. newspa ...
Published 10:00 pm PST, Monday, January 16, 2006 * {{Authority control Neurotoxins Plant toxins Analgesics Total synthesis Terpenes and terpenoids Carboxylate esters Orthoesters Benzyl compounds Cyclopentenes