Sorrento Therapeutics has been developing RTX as a means to provide pain relief for forms of advanced cancer. It causes severe burning pain in sub-microgram (less than 1/1,000,000th of a gram) quantities when ingested orally. Animal experiments on rats suggest that, in humans, ingestion of 1.672 g may be fatal or cause serious damage to health. For rats, LD50 through oral ingestion is 148.1 mg/kg. 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. The primary action of resiniferatoxin is to activate sensory neurons responsible for the perception of pain. Toxicity Īt 16 billion Scoville units, resiniferatoxin is rather toxic and can inflict chemical burns in minute quantities. It has been proposed by the Inoue group of the University of Tokyo. Īn 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.
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. 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. 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. It reacts through an oxidopyrylium cycloaddition when heated with DBU in acetonitrile to form Structure 4 by way of Intermediate 3. Structure 2 contains the first ring of the three-ring structure of RTX. 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. The Wender group was able to form the first ring of the structure by first synthesizing Structure 1 in Figure 1. One of the main challenges in synthesizing a molecule such as resiniferatoxin is forming the three-ring backbone of the structure. As of 2007, this represented the only complete total synthesis of any member of the daphnane family of molecules. The process begins with a starting material of 1,4-pentadien-3-ol and consists of more than 25 significant steps.
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This partial synthesis shows how to create the three-ring backbone of RTXĪ total synthesis of (+)-resiniferatoxin was completed by the Wender group at Stanford University in 1997. A partial synthesis of a resiniferatoxin derivative based on the method put forth by the Wender group of Stanford University. This stimulation is followed by desensitization and analgesia, in part because the nerve endings die from calcium overload. 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. 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. Resiniferatoxin activates transient vanilloid receptor 1 (TRPV1) in a subpopulation of primary afferent sensory neurons involved in nociception, the transmission of physiological pain. Resiniferatoxin has a score of 16 billion Scoville heat units, making pure resiniferatoxin about 500 to 1000 times hotter than pure capsaicin. It is a potent functional analog of capsaicin, the active ingredient in chili peppers. 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. Above peak ( highly toxic from pungency as defined by TRPV1 activation)
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