Resiniferatoxin

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Resiniferatoxin
Resiniferatoxin.svg
Names
IUPAC name
[(1R,2R,6R,10S,11R,13R,15R,17R)-13-Benzyl-6-hydroxy-4,17-dimethyl-5-oxo-15-(prop-1-en-2-yl)-12,14,18-trioxapentacyclo[11.4.1.01,10.02,6.011,15]octadeca-3,8-dien-8-yl]methyl 2-(4-hydroxy-3-methoxyphenyl)acetate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
MeSH resiniferatoxin
PubChem CID
UNII
  • InChI=1S/C37H40O9/c1-21(2)35-17-23(4)37-27(33(35)44-36(45-35,46-37)19-24-9-7-6-8-10-24)14-26(18-34(41)30(37)13-22(3)32(34)40)20-43-31(39)16-25-11-12-28(38)29(15-25)42-5/h6-15,23,27,30,33,38,41H,1,16-20H2,2-5H3/t23-,27+,30-,33-,34-,35-,36-,37-/m1/s1 X mark.svgN
    Key: DSDNAKHZNJAGHN-MXTYGGKSSA-N Yes check.svgY
  • C[C@@H]1C[C@]2([C@H]3[C@H]4[C@]1([C@@H]5C=C(C(=O)[C@]5(CC(=C4)COC(=O)Cc6ccc(c(c6)OC)O)O)C)O[C@](O3)(O2)Cc7ccccc7)C(=C)C
Properties
C37H40O9
Molar mass 628.718 g·mol−1
Density 1.35 ± 0.1 g/cm3
insoluble in water and hexane, soluble in ethyl acetate, ethanol, methanol, acetone, chloroform, and dichloromethane.
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)
Resiniferatoxin
HeatAbove peak (highly toxic from pungency as defined by TRPV1 activation)
Scoville scale 16,000,000,000 SHU

Resiniferatoxin (RTX) is a naturally occurring chemical found in resin spurge ( Euphorbia resinifera ), a cactus-like plant commonly found in Morocco, and in Euphorbia poissonii found in northern Nigeria. [1] It is a potent functional analog of capsaicin, the active ingredient in chili peppers. [2]

Biological activity

Resiniferatoxin has a score of 16 billion Scoville heat units, making pure resiniferatoxin about 500 to 1000 times hotter than pure capsaicin. [3] [4] Resiniferatoxin activates transient vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in nociception, the transmission of physiological pain. [5] [6] 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, especially calcium. 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, in part because the nerve endings die from calcium overload. [7] [8]

Total synthesis

A total synthesis of (+)-resiniferatoxin was completed by the Paul Wender group at Stanford University in 1997. [9] 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. [10]

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 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. [9]

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. [11] [12]

Figure 1. A partial synthesis of a resiniferatoxin derivative based on the method put forth by the Wender group of Stanford University. This partial synthesis shows how to create the three-ring backbone of RTX RTX partial synthesis.jpg
Figure 1. A partial synthesis of a resiniferatoxin derivative based on the method put forth by the Wender group of Stanford University. This partial synthesis shows how to create the three-ring backbone of RTX

Toxicity

At 16 billion Scoville units, resiniferatoxin is rather toxic and can inflict chemical burns 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, [13] with ~500x higher binding affinity for TRPV1 than capsaicin, the active ingredient in hot chili peppers such as those produced by Capsicum annuum . It is 3 to 4 orders of magnitude more potent than capsaicin for effects on thermoregulation and neurogenic inflammation. [14] For rats, LD50 through oral ingestion is 148.1 mg/kg. [15] 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. [16] [17]

The nerve desensitizing properties of RTX were once thought to be useful to treat overactive bladder (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 approval for this use. [4] RTX has also previously been investigated as a treatment for interstitial cystitis, rhinitis, and lifelong premature ejaculation (PE). [17] [18]

See also

Related Research Articles

<span class="mw-page-title-main">Capsaicin</span> Pungent chemical compound in chili peppers

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) 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 in any tissue with which it comes into contact. Capsaicin and several related amides (capsaicinoids) are produced as secondary metabolites by chili peppers, likely as deterrents against certain mammals and fungi. Pure capsaicin is a hydrophobic, colorless, highly pungent crystalline solid.

<span class="mw-page-title-main">Thermoreceptor</span> Receptive portion of a sensory neuron

A thermoreceptor is a non-specialised sense receptor, or more accurately the receptive portion of a sensory neuron, that codes absolute and relative changes in temperature, primarily within the innocuous range. In the mammalian peripheral nervous system, warmth receptors are thought to be unmyelinated C-fibres, while those responding to cold have both C-fibers and thinly myelinated A delta fibers. The adequate stimulus for a warm receptor is warming, which results in an increase in their action potential discharge rate. Cooling results in a decrease in warm receptor discharge rate. For cold receptors their firing rate increases during cooling and decreases during warming. Some cold receptors also respond with a brief action potential discharge to high temperatures, i.e. typically above 45 °C, and this is known as a paradoxical response to heat. The mechanism responsible for this behavior has not been determined.

Transient receptor potential 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, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

Euphorbium, an acrid dull-yellow or brown resin, consisting of the concreted milky juice of several species of Euphorbia, cactus-like perennial plants indigenous to Morocco. It dissolves in alcohol, ether and turpentine; in water it is only slightly soluble. It consists of two or more resins and a substance euphorbone, C20H36O or C15H24O. Pliny the Elder states that the name of the drug was given to it in honor of Euphorbus, the physician of Juba II, king of Mauretania. In former times euphorbium was valued in medicine for its drastic, purgative and emetic properties.

<i>Euphorbia resinifera</i> Species of plant

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 potent capsaicin analog tested as an analgesic since 1997.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">TRPV</span> Subgroup of TRP cation channels named after the vanilloid receptor

TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.

<span class="mw-page-title-main">Capsazepine</span> Chemical compound

Capsazepine is a synthetic antagonist of capsaicin. It is used as a biochemical tool in the study of TRPV ion channels.

<span class="mw-page-title-main">Group C nerve fiber</span> One of three classes of nerve fiber in the central nervous system and peripheral nervous system

Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The C group fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A and B are myelinated. Group C fibers include postganglionic fibers in the autonomic nervous system (ANS), and nerve fibers at the dorsal roots. These fibers carry sensory information.

<span class="mw-page-title-main">Tinyatoxin</span> Chemical compound

Tinyatoxin is an analog of the neurotoxin resiniferatoxin. It occurs naturally in Euphorbia poissonii.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<i>Euphorbia poissonii</i> Species of plant

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. It is native to northern Nigeria, where local farmers extract its latex for use as a pesticide. Its powerfully irritant and pain-producing nature mandates use as a fencing plant. It is known to the Berom people of the Jos area as pyùlúp who transplant it to their compounds where it is regarded as protection against witchcraft.

Hydroxy-<i>alpha</i>-sanshool Chemical compound

Hydroxy-alpha-sanshool is a molecule found in plants from the genus Zanthoxylum. It is believed to be responsible for the numbing and tingling sensation caused by eating food cooked with Sichuan peppercorns and Uzazi.

<span class="mw-page-title-main">Iodoresiniferatoxin</span> Chemical compound

Iodoresiniferatoxin (I-RTX) is a strong competitive antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX).

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is a ligand gated ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990; since then, several TRPV1 antagonists have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain, then this class of compounds may offer one of the first novel mechanisms for the treatment of pain in many years.

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. Zucapsaicin is a member of phenols and a member of methoxybenzenes. It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1 that reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

<span class="mw-page-title-main">Vanillotoxin</span> Chemical compound

Vanillotoxins are neurotoxins found in the venom of the tarantula Psalmopoeus cambridgei. They act as agonists for the transient receptor potential cation channel subfamily V member 1 (TRPV1), activating the pain sensory system. VaTx1 and 2 also act as antagonists for the Kv2-type voltage-gated potassium channel (Kv2), inducing paralytic behavior in small animals.

<span class="mw-page-title-main">Vanilloid</span> Chemical compounds containing a vanillyl group

The vanilloids are compounds which possess a vanillyl group. They include vanillyl alcohol, vanillin, vanillic acid, acetovanillon, vanillylmandelic acid, homovanillic acid, capsaicin, etc. Isomers are the isovanilloids.

RhTx is a small peptide toxin from Scolopendra subspinipes mutilans, also called the Chinese red-headed centipede. RhTx binds to the outer pore region of the temperature regulated TRPV1 ion channel, preferably in activated state, causing a downwards shift in the activation threshold temperature, which leads to the immediate onset of heat pain.

<span class="mw-page-title-main">Phenylacetylrinvanil</span> Chemical compound

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 is an amide of vanillylamine and ricinoleic acid, with the hydroxyl group on ricinoleic acid esterified with phenylacetic acid. It is used to study the function of the TRPV1 receptor and its downstream actions, and has also shown anti-cancer effects in vitro.

References

  1. ↑ Euphorbia poissonii in BoDD – Botanical Dermatology Database
  2. ↑ Walpole CS, Bevan S, Bloomfield G, Breckenridge R, James IF, Ritchie T, et al. (July 1996). "Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues". Journal of Medicinal Chemistry. 39 (15): 2939–2952. doi:10.1021/jm960139d. PMID   8709128.
  3. ↑ National Institutes of Health, Clinical Center Department of Perioperative Medicine Chemical from cactus-like plant shows promise in controlling surgical pain, while leaving touch and coordination intact, rat study shows News release December 21, 2017, retrieved 28 February 2018.
  4. 1 2 Ellsworth P, Wein AJ (2009). Questions and Answers about Overactive Bladder. Jones & Bartlett Learning. pp. 97–100. ISBN   978-1449631130.
  5. ↑ Szallasi A, Blumberg PM (1989). "Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper". Neuroscience. 30 (2): 515–520. doi:10.1016/0306-4522(89)90269-8. PMID   2747924. S2CID   24829016.
  6. ↑ Szallasi A, Blumberg PM (1990). "Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor". Life Sciences. 47 (16): 1399–1408. doi:10.1016/0024-3205(90)90518-V. PMID   2174484.
  7. ↑ Szallasi A, Blumberg PM (June 1992). "Vanilloid receptor loss in rat sensory ganglia associated with long term desensitization to resiniferatoxin". Neuroscience Letters. 140 (1): 51–54. doi:10.1016/0304-3940(92)90679-2. PMID   1407700. S2CID   9429182.
  8. ↑ Olah Z, Szabo T, Karai L, Hough C, Fields RD, Caudle RM, et al. (April 2001). "Ligand-induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1". The Journal of Biological Chemistry. 276 (14): 11021–11030. doi: 10.1074/jbc.M008392200 . hdl: 2437/104771 . PMID   11124944.
  9. 1 2 Wender PA, Jesudason CD, Nakahira H, Tamura N, Tebbe AL, Ueno Y (1997). "The First Synthesis of a Daphnane Diterpene: The Enantiocontrolled Total Synthesis of (+)-Resiniferatoxin". J. Am. Chem. Soc. 119 (52): 12976–12977. doi:10.1021/ja972279y.
  10. ↑ Seiple IB (March 17, 2007). "Daphnane, Tigliane, Ingenane and Lathyrane Diterpenes" (PDF). scripps.edu.
  11. ↑ "Resiniferatoxin– A Radical Approach". Chemical Science Blog. Royal Society of Chemistry.
  12. ↑ Murai K, Katoh SI, Urabe D, Inoue M (2013). "A radical-based approach for the construction of the tetracyclic structure of resiniferatoxin". Chemical Science. 4 (6): 2364. doi:10.1039/C3SC50329A.
  13. ↑ Raisinghani M, Pabbidi RM, Premkumar LS (September 2005). "Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin". The Journal of Physiology. 567 (Pt 3): 771–786. doi:10.1113/jphysiol.2005.087874. PMC   1474234 . PMID   16037081.
  14. ↑ Szallasi A, Blumberg P (1989). "Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper". Neuroscience. 30 (2): 515–520. doi:10.1016/0306-4522(89)90269-8.
  15. ↑ "Material Safety Data Sheet for resiniferatoxin, 2009" (PDF).
  16. ↑ Brown DC (August 2016). "Resiniferatoxin: The Evolution of the "Molecular Scalpel" for Chronic Pain Relief". Pharmaceuticals. 9 (3): 47. doi: 10.3390/ph9030047 . PMC   5039500 . PMID   27529257.
  17. 1 2 "Resiniferatoxin - Sorrento Therapeutics". AdisInsight. Springer Nature Switzerland AG. 2019-01-24.
  18. ↑ Shi B, Li X, Chen J, Su B, Li X, Yang S, et al. (September 2014). "Resiniferatoxin for treatment of lifelong premature ejaculation: a preliminary study". International Journal of Urology. 21 (9): 923–926. doi:10.1111/iju.12471. PMID   24912663. S2CID   23297142.
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