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Resiniferatoxin
Names
IUPAC name
[(1R,6R,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
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 ☒N
    Key: DSDNAKHZNJAGHN-YTRLEMBBSA-N checkY
  • InChI=1/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
    Key: DSDNAKHZNJAGHN-YTRLEMBBBO
  • Oc1ccc(cc1OC)CC(=O)OCC=4C[C@]7(O)C(=O)C(\C)=C/C7[C@]52O[C@@]3(O[C@](C[C@H]2C)(C(C)=C)C(O3)C5C=4)Cc6ccccc6
Properties
C37H40O9
Molar mass 628.71 g/mol
Density 1.35 ± 0.1 g/cm³
insoluble
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Tracking categories (test):

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 an ultrapotent analogue of capsaicin, the active ingredient in chili peppers.[2] Having a score of 16 billion Scoville units, pure resiniferatoxin is approximately 1000 times more hot than pure capsaicin.[3] Capsaicin is currently used in some methods of pain relief treatment, and it is currently being investigated whether or not RTX can also be safely and effectively used to treat pain.

Overview[edit]

Resiniferatoxin activates transient vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in nociception (the transmission of physiological pain).[4][5] 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.[6][7]

Uses[edit]

As a substance that causes nerve desensitization and analgesia, resiniferatoxin has been studied for a variety of possible applications, especially in the fields of nociception and urology. It is often studied in conjunction with capsaicin due to the similarity of the two molecules.

Pain Relief[edit]

Currently RTX is being tested to treat pain relief for forms of advanced cancer. Since RTX has been shown to be selective in its ablation of nerves, affecting only the ability to sense pain and not proprioception or other sensations, it is hypothesized that injections of RTX may be able to be used as a "molecular scalpel" and only desensitize the nerves that keep transmitting signals of chronic pain.[8] The National Institute of Dental and Craniofacial Research (NIDCR) is currently sponsoring an ongoing clinical trial to evaluate single injection RTX treatments for patients with late-stage cancer.[9] Previously in 2014, Sorrento Therapeutics (an oncology company collaborating in the clinical trial) announced that the phase I trial successfully showed “clinically meaningful improvement in quality of life” for patients who had received a single injection of resiniferatoxin.[10] Phase II clinical trials began on Jan 11 2016, and the study is expected to continue through Dec 2020.[9][10][11]

Resiniferatoxin has also been investigated as an alternative to opioids in the pain relief treatment of burn victims. A preliminary study has shown that RTX injections in both male and female rats who had sustained thermal injuries resulted in long-lasting analgesia, and that the injections did not prevent the wounds from healing properly.[12]

Other Uses[edit]

One preliminary study has suggested that RTX can cause apoptosis in pancreatic cancer cells, and therefore may also be useful in the treatment of cancer itself in addition to the chronic pain that accompanies it.[13]

Furthermore, Resiniferatoxin has been actively studied in urology. 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. Some studies suggested RTX could produce clinical improvement for patients suffering from OAB, especially since injections of capsaicin to the bladder would cause pain when those of resiniferatoxin would not. However, the treatment of OAB with injections of resiniferatoxin never received FDA approval.[3] RTX has also previously been investigated as a treatment for interstitial cystitis, rhinitis, and lifelong premature ejaculation (PE).[11] It was likely discontinued as a treatment for interstitial cystitis after a preliminary study found RTX treatments to be safe yet ineffective.[14] A preliminary study investigating the use of RTX to treat premature ejaculation also questioned its efficacy as a treatment for PE, and in addition noted that patients "felt a burning sensation."[15]

Additionally, RTX has shown both emetic and anti-emetic effects in multiple animal trials.[16][17]

Total synthesis[edit]

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

A total synthesis of (+)-resiniferatoxin was completed by the Wender group at Stanford University in 1997.[18] The process begins with a starting material of 1,4-pentadiene-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.[19]

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.[18]

An alternative approach to synthesizing the three-ring backbone has been proposed by the Inoue group of the University of Tokyo.[20] This method makes use of radical reactions to create the first and third rings in a single step, followed by the creation of the remaining ring.

Toxicity[edit]

Resiniferatoxin is toxic and can inflict a chemical burning sensation in microscopic 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 to science, with ~500x higher binding affinity for TRPV1 than capsaicin, the active ingredient in hot chili peppers such as those produced by Capsicum annuum. Animal experiments suggest that, in humans, ingestion of 10 g may be fatal or cause serious damage to health.[21] It causes severe burning pain in sub-microgram (less than 1/1,000,000th of a gram) quantities when ingested orally.

See also[edit]

References[edit]

  1. ^ Euphorbia poissonii in BoDD – Botanical Dermatology Database
  2. ^ *Christopher S. J. Walpole; et al. (1996). "Similarities and Differences in the Structure-Activity Relationships of Capsaicin and Resiniferatoxin Analogues". J. Med. Chem. 39 (15): 2939–2952. doi:10.1021/jm960139d. PMID 8709128.
  3. ^ a b Ellsworth, Pamela; Wein, Alan J. (2009). Questions and Answers about Overactive Bladder. Jones & Bartlett Learning. p. 97-100. ISBN 1449631134.
  4. ^ Szallasi A, Blumberg PM (1989). "Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analogue of capsaicin, the irritant constituent in red pepper". Neuroscience. 30 (2): 515–520. doi:10.1016/0306-4522(89)90269-8. PMID 2747924.
  5. ^ Szallasi A, Blumberg PM (1990). "Resiniferatoxin and its analogues provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor". Life Sci. 47 (16): 1399–1408. doi:10.1016/0024-3205(90)90518-V.
  6. ^ Szallasi A, Blumberg PM (1992). "Vanilloid receptor loss in rat sensory ganglia associated with long term desensitization to resiniferatoxin". Neurosci Lett. 140 (1): 51–54. doi:10.1016/0304-3940(92)90679-2. PMID 1407700.
  7. ^ Olah Z, et al. (2001). "Ligand-induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1". J. Biol. Chem. 276 (14): 11021–11030. doi:10.1074/jbc.M008392200. PMID 11124944.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Brown, D.C. (2016). "Resiniferatoxin: The Evolution of the 'Molecular Scalpel' for Chronic Pain Relief". Pharmaceuticals. 9 (3): 47. doi:10.3390/ph9030047. PMID 5039500.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ a b https://clinicaltrials.gov/ct2/show/NCT00804154
  10. ^ a b http://www.prnewswire.com/news-releases/sorrento-announces-presentation-of-data-from-clinical-study-of-resiniferatoxin-for-intractable-cancer-pain-at-asra-meeting-253869581.html
  11. ^ a b http://adisinsight.springer.com/drugs/800009782
  12. ^ Salas, M.M.; et al. (2016). "Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury". Pain Med. doi:10.1093/pm/pnw260. {{cite journal}}: Explicit use of et al. in: |author= (help)
  13. ^ Hartel, M; et al. (2006). "Vanilloids in pancreatic cancer: potential for chemotherapy and pain management". Gut. 55 (4): 519–528. doi:10.1136/gut.2005.073205. PMID 1856157. {{cite journal}}: Explicit use of et al. in: |author= (help)
  14. ^ https://www.ics.org/Abstracts/Publish/42/000148.pdf
  15. ^ Bentao, S.; et al. (2014). "Resiniferatoxin for treatment of lifelong premature ejaculation: A preliminary study". International Journal of Urology. 21 (9): 923–926. doi:10.1111/iju.12471. {{cite journal}}: Explicit use of et al. in: |author= (help)
  16. ^ Andrews, P.L.R.; et al. (2000). "The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus Murinus, the house musk shrew". British Journal of Pharmacology. 130 (6): 1247–1254. doi:10.1038/sj.bjp.0703428. {{cite journal}}: Explicit use of et al. in: |author= (help)
  17. ^ Yamakuni, H.; et al. (2002). "Resiniferatoxin antagonizes cisplatin-induced emesis in dogs and ferrets". European Journal of Pharmacology. 442 (3): 273–278. doi:10.1016/S0014-2999(02)01541-8. PMID 12065081. {{cite journal}}: Explicit use of et al. in: |author= (help)
  18. ^ a b Wender, P.A.; Jesudason, Cynthia D.; Nakahira, Hiroyuki; Tamura, Norikazu; Tebbe, Anne Louise; Ueno, Yoshihide (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.
  19. ^ http://www.scripps.edu/chem/baran/images/grpmtgpdf/Seiple_Mar_07.pdf
  20. ^ http://blogs.rsc.org/sc/2013/03/29/resiniferatoxin/
  21. ^ Material Safety Data Sheet for resiniferatoxin, 2009

External links[edit]

Category:Neurotoxins Category:Plant toxins Category:Analgesics Category:Total synthesis Category:Terpenes and terpenoids Category:Carboxylate esters Category:Orthoesters

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