Resiniferatoxin has a score of 16 billionScoville heat units, making pure resiniferatoxin about 500 to 1000 times hotter than purecapsaicin.[3][4] Resiniferatoxin activatestransient vanilloid receptor 1 (TRPV1) in a subpopulation of primaryafferent sensory neurons involved innociception, the transmission ofphysiological 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 tocations, especiallycalcium. 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 andanalgesia, in part because the nerve endings die from calcium overload.[7][8]
Atotal synthesis of (+)-resiniferatoxin was completed by thePaul Wender group atStanford 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 withm-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 withDBU inacetonitrile 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 theallylic branch of the seven-membered ring in atrans conformation. Once this conformation is achieved, zirconocene-mediated cyclization of Structure 5 can occur, and oxidizing the resulting hydroxy group withTPAP 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 theUniversity 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
At 16 billion Scoville units, resiniferatoxin is toxic and can inflictchemical 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 a binding affinity for TRPV1 about 500 times higher than purecapsaicin, the active ingredient in hot chili peppers such as those produced byCapsicum annuum. It is 1000-10,1000 times more potent than capsaicin for effects onthermoregulation andneurogenic 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.
The nerve desensitizing properties of RTX were once thought to be useful to treatoveractive 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 receivedFederal Drug Administration approval for this use.[4] RTX has also previously been investigated as a treatment forinterstitial cystitis,rhinitis, and lifelongpremature ejaculation (PE).[16][17]
^abWender 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.
^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.
^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.PMID24912663.S2CID23297142.
