4 Clinically Useful Vanilloid Receptor TRPV1 Antagonists: Just around the Corner (or too Early to Tell)?

A subset of sensory nerves (those with un-myelinated axons) is characterized by a unique sensitivity to capsaicin (1), the piquant ingredient in hot chilli peppers. The excitation of these nerves is followed by a lasting refractory state, traditionally referred to as desensitization, or, under certain conditions such as neonatal treatment, by gross neurotoxicity [1]. Capsaicin-sensitive nerves function as polymodal nociceptors (their activators include noxious heat, inflammatory 'soup' and pungent compounds such as capsaicin, piperine, zingerone, but not mechanical pressure) and convey pain into the central nervous system (CNS) [1, 2]. Moreover, these nerves are involved in various reflex responses (micturition and cough being prominent examples) as well as local neurogenic inflammatory and vasoregulator functions [2]. These latter functions are mediated by sensory neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), stored in and released from capsaicin-sensitive nerves [3]. Desensitization to capsaicin has a clear therapeutical potential. In fact, capsaicin-containing creams (e.g. Zostrix and Axsain) have been in clinical use for decades for indications such as diabetic neuropathy, postmastectomy pain syndrome and postherpetic neuralgia [1]. In 1990, specific binding of [³H]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 VR1 [1]. The molecular cloning of the rat capsaicin receptor [5], subsequently re-named as the transient receptor potential vanilloid receptor 1 (TRPV1) [6], has fuelled intensive research into its physiology and resulted in the discovery of small molecule TRPV1 antagonists [7, 8]. This breakthrough discovery was followed by the cloning and pharmacological characterization of the human [9, 10], guinea pig [11], rabbit [12], avian [13] and mouse [14] homologues of TRPV1. Studies with TRPV1-deficient animals confirmed the pivotal role that this receptor plays in the development of postinflammatory hyperalgesia [15, 16]. Now there is good evidence that TRPV1 expression is regulated in humans. As of 2005, diseases with up-regulated TRPV1 include inflammatory bowel disease (IBD) [17], irritable bowel syndrome [18], vulvar allodynia [19] and reflux oesophagitis [20], but this list is expected to grow in the foreseeable future. These findings lend further support to the notion that TRPV1 ligands could be clinically useful analgesic, anti-inflammatory drugs. At present, two conceptually different (but not mutually exclusive) therapeutic strategies are being pursued in the vanilloid field: one is to use optimized TRPV1 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 TRPV1 [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]. The therapeutic potential of TRPV1 agonists has recently been subject to excellent and exhaustive reviews [21, 23, 24] and, consequently, will not be dealt within this paper. Instead, we focus on the proliferating number of small molecule TRPV1 antagonists. Although the therapeutic utility of TRPV1 antagonists was recently discussed both by us [7] and others [8], the rapid advances in this field necessitate frequent re-evaluation. Chronic neuropathic pain is debilitating to patients and its management is frustrating for physicians. The recent withdrawal of COX-2 inhibitors from the market has further emphasized the need for new classes of safe and effective analgesic, anti-inflammatory drugs. Whether TRPV1 antagonists can be such drugs, this is the question we attempt to answer here.