Resiniferatoxin

Synthesis of paclitaxel and resiniferatoxin analogs, diterpenoids with oxetane fragments 97G461. 

Resiniferatoxin (RTX) is the toxin isolated from the spurge Euphorbia resinifera which is responsible for the powerful burning sensation and skin irritation induced by the milky sap of these plants. Like capsaicin, resiniferatoxin activates TRPV1 currents, but not the currents through other members ofthe TRPV subfamily. 

TRPVl, also known as the capsaicin- or vanilloid-receptor, is a nonselective cation channel expressed e.g., in neurons of the dorsal root and trigeminal ganglions, which integrates multiple pain-producing stimuli including heat, protons, capsaicin, and resiniferatoxin. In addition, TRPVl currents can be activated by ananda-mide, protein kinase C (PKC), and by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). 

In 1990, specific binding of [ H]resiniferatoxin (2, RTX), an ultrapotent capsaicin analogue isolated from the latex of the cactus-like plant Euphorbia resinifera, provided the first direct proof for the existence of a distinct capsaicin receptor [4]. Based on the chemical motif (a vanillyl moiety) shared by (1) and (2), this receptor was termed the vanilloid receptor VRl [1]. 

Resiniferatoxin-induced systemic vascular leakage (SYVAL). 

Scheme 1 Chemical structures of natural vanilloid receptor agonists a, capsaicin, the irritant principle in hot peppers b, resiniferatoxin (RTX), isolated from the cactuslike plant Euphorbia resinifera c, the triprenyl phenol scutigeral, found in an edible, non-pungent mushroom d, the sesquiterpenoid dialdehyde isovelleral, found in pungent mushrooms.

Resiniferatoxin (RTX) is a daphnane diterpenoid contained in the irritant latex of some succulent African Euphorbias. Its total synthesis has been described as a 40 step asymmetric synthesis (Wender et al., 1997 see below), but for clinical use RTX isolated from Euphorbia resinifera. 

Clinical use Resiniferatoxin has been characterized as an ultrapotent sensory neuron desensitizing agent. It is 100 to 10,000 times more potent than capsaicin, has a longer duration of action, is much less irritating, and is substantially more effective in producing neural... 

Scheme 5 Chemical structures of known vanilloid receptor antagonists a, capsazepine, a weak but competitive synthetic compound from Novartis, b, iodo-resiniferatoxin, a potent and competitive synthetic compound from Novo Nordisk, c, ruthenium red, a weak, non-competitive and non-selective antagonists.

Acs, G., Palkovits, M., Blumberg, P.M. Specific binding of [3H]resiniferatoxin by human and rat preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus membrane preparations, Life Sci. 1996, 59, 1899-1908. 

Chancellor, M B. and de Groat, W.C. Intravesical capsaicin and resiniferatoxin therapy spicing up the ways to treat the overactive bladder, J. Urology 1999, 162, 3-11. 

Cruz, F., Guimaraes, M., Silva, C., Reis M. Suppression of bladder hyperreflexia by intravesical resiniferatoxin, Lancet 1997, 350, 640-641. 

Lazzeri, M., Spinelli, M., Beneforti, P., Zanollo, A., Turini, D. Intravesical resiniferatoxin for the treatment of detrusor hyperreflexia refractory to capsaicin in patients with chronic spinal cord diseases, Scandinavian J. Urol. Nephrol. 1998, 32, 331-334. 

Szallasi, A. and Blumberg, P.M. Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes, Brain Res. 1990a, 524, 106-111. 

Wahl, P., Foged, C., Tullin, S., Thomsen, C. lodo-resiniferatoxin, a new potent vanilloid receptor antagonist, Mol. Pharmacol. 2001, 59, 9-15. 

Winter, J., Walpole, C.S., Bevan, S., James, I.F Characterization of resiniferatoxin binding sites on sensory neurons co-regulation of resiniferatoxin binding and capsaicin sensitivity in adult rat dorsal root ganglia, Neuroscience 1993, 57, 747-757. 

In the course of a total synthesis of resiniferatoxin, an unexpected ring extension occurred, when 1,3-dioxane 236a was treated with an acid in chloroform. The ring extension was confirmed by acid-catalyzed rearrangement of diol 236b into dioxepane 237 (Scheme 70) <20040L4371>. 

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