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]
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, with ~500x higher binding affinity for TRPV1 than
capsaicin, the active ingredient in hot chili peppers such as those produced by Capsicum annuum. For rats,
LD50 through oral ingestion is 148.1 mg/kg.[13] 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 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).[15][16]
^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.
PMID8709128.
^
abWender, 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.
^Murai, Koichi; Katoh, Shun-Ichiroh; Urabe, Daisuke; Inoue, Masayuki (2013). "A radical-based approach for the construction of the tetracyclic structure of resiniferatoxin". Chemical Science. 4 (6): 2364.
doi:
10.1039/C3SC50329A.