Resiniferatoxin

Resiniferatoxin has a score of 16 billion Scoville heat units, making pure resiniferatoxin about 500 to 1000 times hotter than pure capsaicin.National Institutes of Health, Clinical Center Department of Perioperative Medicine [https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2667622 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. Resiniferatoxin activates transient vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in nociception, the transmission of physiological pain.{{cite journal | vauthors = Szallasi A, Blumberg PM | title = Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper | journal = Neuroscience | volume = 30 | issue = 2 | pages = 515–520 | year = 1989 | pmid = 2747924 | doi = 10.1016/0306-4522(89)90269-8 | s2cid = 24829016 | url = https://zenodo.org/record/1258479 }}{{cite journal | vauthors = Szallasi A, Blumberg PM | title = Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor | journal = Life Sciences | volume = 47 | issue = 16 | pages = 1399–1408 | year = 1990 | pmid = 2174484 | doi = 10.1016/0024-3205(90)90518-V | url = https://zenodo.org/record/1254103 }} 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.{{cite journal | vauthors = Szallasi A, Blumberg PM | title = Vanilloid receptor loss in rat sensory ganglia associated with long term desensitization to resiniferatoxin | journal = Neuroscience Letters | volume = 140 | issue = 1 | pages = 51–54 | date = June 1992 | pmid = 1407700 | doi = 10.1016/0304-3940(92)90679-2 | s2cid = 9429182 | url = https://zenodo.org/record/1258465 }}{{cite journal | vauthors = Olah Z, Szabo T, Karai L, Hough C, Fields RD, Caudle RM, Blumberg PM, Iadarola MJ | title = Ligand-induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 14 | pages = 11021–11030 | date = April 2001 | pmid = 11124944 | doi = 10.1074/jbc.M008392200 | hdl-access = free | doi-access = free | hdl = 2437/104771 }}

A total synthesis of (+)-resiniferatoxin was completed by the Paul Wender group at Stanford University in 1997.{{cite journal | vauthors = Wender PA, Jesudason CD, Nakahira H, Tamura N, Tebbe AL, Ueno Y | title = The First Synthesis of a Daphnane Diterpene: The Enantiocontrolled Total Synthesis of (+)-Resiniferatoxin | journal = J. Am. Chem. Soc. | year = 1997 | volume = 119 | issue = 52 | pages = 12976–12977 | doi = 10.1021/ja972279y| bibcode = 1997JAChS.11912976W }} 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.{{cite web |url=https://www.scripps.edu/baran/images/grpmtgpdf/Seiple_Mar_07.pdf |title=Daphnane, Tigliane, Ingenane and Lathyrane Diterpenes| vauthors = Seiple IB |date= March 17, 2007|website=scripps.edu}}

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.

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.{{cite web|url=http://blogs.rsc.org/sc/2013/03/29/resiniferatoxin/|title=Resiniferatoxin– A Radical Approach | work = Chemical Science Blog| publisher = Royal Society of Chemistry }}{{cite journal | vauthors = Murai K, Katoh SI, Urabe D, Inoue M |doi=10.1039/C3SC50329A |title=A radical-based approach for the construction of the tetracyclic structure of resiniferatoxin |date=2013 |journal=Chemical Science |volume=4 |issue=6 |page=2364 }}

File:RTX partial synthesis.jpg

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,{{cite journal | vauthors = Raisinghani M, Pabbidi RM, Premkumar LS | title = Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin | journal = The Journal of Physiology | volume = 567 | issue = Pt 3 | pages = 771–786 | date = September 2005 | pmid = 16037081 | pmc = 1474234 | doi = 10.1113/jphysiol.2005.087874 }} with ~500x higher binding affinity for TRPV1 than pure 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.{{Cite journal |last1=Szallasi |first1=A. |last2=Blumberg |first2=P.M. |date=1989 |title=Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper |url=https://linkinghub.elsevier.com/retrieve/pii/0306452289902698 |journal=Neuroscience |language=en |volume=30 |issue=2 |pages=515–520 |doi=10.1016/0306-4522(89)90269-8|pmid=2747924 }} For rats, LD50 through oral ingestion is 148.1 mg/kg.{{cite web|url=http://datasheets.scbt.com/sc-24015.pdf|title= Material Safety Data Sheet for resiniferatoxin, 2009}} It causes severe burning pain in sub-microgram (less than 1/1,000,000th of a gram) quantities when ingested orally.

Sorrento Therapeutics has been developing RTX as a means to provide pain relief for forms of advanced cancer.{{cite journal | vauthors = Brown DC | title = Resiniferatoxin: The Evolution of the "Molecular Scalpel" for Chronic Pain Relief | journal = Pharmaceuticals | volume = 9 | issue = 3 | pages = 47 | date = August 2016 | pmid = 27529257 | pmc = 5039500 | doi = 10.3390/ph9030047 | doi-access = free }}{{cite web|url=https://adisinsight.springer.com/drugs/800009782|title=Resiniferatoxin - Sorrento Therapeutics | work = AdisInsight| publisher = Springer Nature Switzerland AG | date = 2019-01-24}}

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.{{cite book | vauthors = Ellsworth P, Wein AJ | date = 2009 | title = Questions and Answers about Overactive Bladder | publisher = Jones & Bartlett Learning | pages = 97–100 | isbn = 978-1449631130|url=https://books.google.com/books?id=4WhpvPMZOJUC}} RTX has also previously been investigated as a treatment for interstitial cystitis, rhinitis, and lifelong premature ejaculation (PE).{{cite journal | vauthors = Shi B, Li X, Chen J, Su B, Li X, Yang S, Guan Z, Wang R | title = Resiniferatoxin for treatment of lifelong premature ejaculation: a preliminary study | journal = International Journal of Urology | volume = 21 | issue = 9 | pages = 923–926 | date = September 2014 | pmid = 24912663 | doi = 10.1111/iju.12471 | s2cid = 23297142 }}

• Discovery and development of TRPV1 antagonists
• Iodoresiniferatoxin
• List of investigational analgesics
• Phenylacetylrinvanil
• Transient receptor potential
• Tinyatoxin

{{Reflist}}

• [https://www.seattlepi.com/lifestyle/health/article/Fiery-pepper-may-hold-key-to-easing-pain-1192896.php "Fiery Pepper May Hold Key to Easing Pain"]. Lauran Neergaard, Associated Press, 16 January 16, 2006.
• {{PubChem|Resiniferatoxin}}

{{Toxins}}

{{Transient receptor potential channel modulators}}

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Category:Analgesics

Category:Benzyl compounds

Category:Carboxylate esters

Category:Cyclopentenes

Category:Neurotoxins

Category:Orthoesters

Category:Plant toxins

Category:Terpenes and terpenoids

Category:Total synthesis

Category:Transient receptor potential channel modulators