Resiniferatoxin

For other uses, see RTX.

Resiniferatoxin
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
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-MXTYGGKSSA-N checkY
  • 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).
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Resiniferatoxin
HeatAbove peak (highly toxic from pungency as defined by TRPV1 activation)
Scoville scale16,000,000,000 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

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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

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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

Toxicity

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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 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.[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

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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

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References

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  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. ^ a b 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. ^ a b 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. Bibcode:1997JAChS.11912976W. 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. PMID 2747924.
  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. ^ a b "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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