Vanilloids

Szallasi A, Cortright DN, Blum CA et al (2007) The vanilloid receptor TRPV1 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6 357-372... 

Capsaicin, also known as N-Vanillyl-8-methyl-6-(E)-noneamide, is the most pungent of the group of compounds called capsaicinoids It is a common ingredient in varieties of pepper such as habanero, Thai, tabasco, cayenne etc. One target with which capsaicin interacts is the capsaicin receptor, an ion channel belonging to the superfamily of TRP channels. Because of the structural relation to other TRP channels and because the vanilloid moiety is an essential component of capsaicin, the capsaicin receptor is also called TRPVI or vanilloid receptor (VR1). It is involved in heat and pain perception. 

These are a subset of sensory neurons having their cell bodies (small to medium size) in dorsal root and in cranial nerve ganglia and possessing nonmyelinated (C-type) or thinly myelinated (A-delta type) fibres. This subset of neurons express transient receptor potential vanilloid type 1 (TRPV1, or vanilloid, or capsaicin receptor) that is excited by capsaicin, the pungent ingredient of chilli. These neurons have been classified as polymodal nociceptors because they can be excited by various noxious stimuli. 

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). 

Clinically Useful Vanilloid Receptor TRPVl Antagonists Just around the Corner (or too Early to Tell) ... 

CLINICALLY USEFUL VANILLOID RECEPTOR TRPVl ANTAGONISTS... 

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]. 

At present, two conceptually different (but not mutually exclusive) therapeutic strategies are being pursued in the vanilloid field one is to use optimized TRPVl agonists to desensitize (in practice, defunctionalize) capsaicin-sensitive nerves [1, 21] and the other is to employ small molecule antagonists for the pharmacological blockade of TRPVl [7, 8]. The first approach is time-proven, but is riddled by known side-effects such as pain [1], as well as emerging concerns such as impaired control of cancerous growth [22]. 

Fig. 4.1 Topological organization of the vanilloid receptor TRP VI. Highlighted are the molecular determinants of TRPVl regulation, such as recognition (binding) domains for capsaicin and acids, and phosphorylation sites for protein kinases. Numbers designate the key amino acid residues deduced from the rTRPVl primary sequence. Adapted from Ferrer-Montaniel, A. et al. (2004) Fur. J. Biochem. 271, 1820—1826.

TRPVl splice variant (termed hTRPVlb) was identified that is activated by heat, but not by vanilloids or protons [62]. 

The first vanilloid receptor antagonist was Ruthenium Red (RR), an inorganic dye [1, 2]. Commercial RR is a mixture of compounds [65] and it remains to be understood... 

Owing to a curious overlap of interest in different laboratories, this class of vanilloid antagonists is better investigated than others with regards to both structure-activity relationships and in vivo profile of activities. 

Compared to other classes of vanilloid antagonists, the 4-hetero-arylpiperazine-1-carboxamides are characterized by the presence of a mildly basic nitrogenous polar head. Based on the published studies [79, 82], the structure-activity relationships of this class of vanilloid antagonists can be summarized as follows ... 

Importantly, (15a) also caused mild hyperthermia, a side-effect that might well arise with other TRPVl-antagonists, and that presumably stems from the inactivation of a constitutionally active endogenous vanilloid pathway. This model is at variance with knock-out (k.o.) TRPVl mice that have normal temperature. Animals born without a certain receptor, however, frequently adapt by developing alternative pathways. Clearly, these observations are worth further investigation for example by using conditional TRPVl k.o. animals. 

Research on the identification of vanilloid antagonists has been pursued more intensively in industry than in academia. Thus, a SciFinder search for new chemical entities endowed with this type of activity pulled out 34 entries from the proprietary literature, and only 14 from journal articles during the period January 2004 June 2006. The patent literature can be difficult to evaluate and compare with the published data. Bioactivity is often not disclosed (or commented), and activity can be broadly claimed for a series of lead structures without specifying their optimal substitution. On the other hand, analysis of the patent literature does not only complement the published data, but also offers a preview of information that will be eventually disclosed and detailed in journals. Given the relevance of proprietary literature in the realm of vanilloids research, the main trends emerging from its analysis will be briefly summarized. 

The expression of TRPVl in the bladder is, however, not restricted to afferent nerves urothelium, detrusor muscle and fibroblasts also express TRPVl in the human bladder [140]. The implication of these findings for intravesical vanilloid therapy is unclear [141], but the increase in TRPVl immunoreactivity in the urothelium in patients with neurogenic detrusor overactivity (that occurs in concert with increased TRPVl in bladder af-ferents) is a very intriguing finding [142]. In the male urogenital system, TRPVl is also present in testicles, prostate and scrotal skin [143], and it was postulated that TRPVl ligands may be beneficial in the treatment of benign prostatic hyperplasia [144]. 

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