Resiniferatoxin
[CAS# 57444-62-9]

Identification

• Classification: Flavors and spices >> Synthetic spice >> Alcoholic spice >> Terpene alcohol
• Name: Resiniferatoxin
• Synonyms: [(1R,2R,6R,10S,11R,13S,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
• Molecular Formula: C₃₇H₄₀O₉
• Molecular Weight: 628.71
• CAS Registry Number: 57444-62-9
• EC Number: 637-354-6
• SMILES: 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)CC6=CC(=C(C=C6)O)OC)O)C)O[C@](O3)(O2)CC7=CC=CC=C7)C(=C)C

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 768.7±60.0 ºC 760 mmHg (Calc.)^*
• Flash point: 240.3±26.4 ºC (Calc.)^*
• Solubility: Soluble 100 mM (DMSO), 50 mM (ethanol) (Expl.)
• Index of refraction: 1.643 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS06 Danger
• Hazard Statements: H301-H314
• Precautionary Statements: P260-P264-P270-P280-P301+P316-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P321-P330-P363-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Skin corrosion	Skin Corr.	1A	H314
Acute toxicity	Acute Tox.	3	H331
Acute toxicity	Acute Tox.	3	H311
Skin irritation	Skin Irrit.	2	H315

Discovory and Applicatios

Resiniferatoxin is a naturally occurring diterpene ester belonging to the daphnane family of compounds, known for its extreme potency as an agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor. It was first isolated from the latex of the Euphorbia resinifera plant, a cactus-like member of the spurge family native to Morocco. The compound was discovered during investigations into the bioactive constituents of Euphorbia species, which were historically used in traditional medicine for their irritant and analgesic properties.

The structure of resiniferatoxin is characterized by a complex polycyclic diterpene backbone, with multiple hydroxyl groups and ester functionalities. It is structurally and functionally related to capsaicin, the active component of chili peppers, but is significantly more potent. Resiniferatoxin binds to the TRPV1 receptor with exceptionally high affinity, causing prolonged activation of the receptor, which is primarily expressed in sensory neurons involved in the detection of noxious heat and inflammatory pain stimuli.

Upon binding to TRPV1, resiniferatoxin induces calcium influx into the neuron, initially causing a burning sensation followed by desensitization and functional ablation of the nerve terminals. This unique mode of action has made resiniferatoxin a valuable tool in neuroscience for studying nociceptive pathways and TRPV1 receptor pharmacology. Its irreversible action on pain-transmitting neurons has led to its investigation as a long-acting analgesic for chronic pain conditions.

One of the most prominent areas of application for resiniferatoxin is in the treatment of severe, intractable pain, such as that associated with advanced cancer. Preclinical and early-phase clinical studies have demonstrated that intrathecal or targeted peripheral administration of resiniferatoxin can selectively ablate TRPV1-expressing neurons, providing prolonged pain relief without affecting other sensory modalities or motor function. This approach offers a non-opioid alternative for pain management and has been evaluated in both canine models and human patients.

The compound has also been explored in the context of neurogenic bladder and other conditions involving hyperactive or hypersensitive sensory neurons. By selectively targeting overactive sensory pathways, resiniferatoxin may help modulate reflexes and symptoms driven by aberrant TRPV1 activity. Its effects are localized and long-lasting, minimizing systemic side effects compared to traditional pharmacological agents.

Due to its high potency and the potential for adverse effects if misused, the clinical use of resiniferatoxin requires precise dosing and controlled administration. It is typically delivered through direct injection to the site of action, such as the dorsal root ganglia, bladder wall, or intrathecal space. This localized application maximizes therapeutic benefit while minimizing systemic toxicity.

In addition to its therapeutic applications, resiniferatoxin has contributed significantly to research on pain pathways and receptor biology. Its use in experimental models has helped elucidate the distribution and function of TRPV1-expressing neurons and has provided insights into the mechanisms of neurogenic inflammation and pain sensitization.

Despite its complexity and the challenges associated with its synthesis, resiniferatoxin remains a compound of high interest in both basic and applied biomedical research. Efforts to develop synthetic analogs and formulations have aimed to harness its analgesic potential while improving safety and ease of administration.

Resiniferatoxin stands as a unique example of a natural product with extreme biological activity that has transitioned from a botanical irritant to a targeted therapeutic agent. Its discovery has had a lasting impact on the understanding and treatment of pain, highlighting the enduring value of natural compounds in drug development.

References

1979. An assay procedure for the comparative irritancy testing of esters in the tigliane and daphnane series. Inflammation, 3(3).
DOI: 10.1007/BF00914178

2005. Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC). International Urogynecology Journal and Pelvic Floor Dysfunction, 16(4).
DOI: 10.1007/s00192-005-1307-4

2017. Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF-Induced Pain-Related Behavior. Mediators of Inflammation, 2017.
DOI: 10.1155/2017/2786427