Current Topics in Medicinal Chemistry - Volume 11, Issue 17, 2011

With 462 reviews over the past decade, Transient Receptor Potential (TRP) channels arguably represent one of today's most extensively reviewed pharmacological targets. The vanilloid (capsaicin) receptor TRPV1 itself has been subject to 271 reviews and was featured in several books since its molecular cloning in 1997. One may ask, somewhat sceptically, why to add another review to this pile? My answer is two-fold. First, our knowledge on TRP channels is rapidly evolving and thus the literature needs constant critical re-evaluation. Second, this special issue is unique in that it attempts to form a coherent picture of the field from the gating physiology of TRP channels through disease-related changes in TRP channels expression to preclinical and clinical studies with compounds targeting TRPV1 for pain relief to emerging therapeutic targets (e.g. TRPA1, TRPV3 and TRPM8) that are co-expressed with TRPV1 on nociceptive neurons. Despite recent advances in our understanding of the mechanisms that cause and maintain pain, chronic pain still represents a major treatment challenge to healthcare providers. The American Pain Society estimates that at least 50 million Americans are affected by chronic pain, rendering many patients partially or totally disabled. Chronic pain already costs the country billions of dollars in health care expenses and lost productivity and the situation will certainly worsen as the population continues to age. Unfortunately, most analgesic drugs on the market today either provide unsatisfactory pain relief or their use is saddled by dangerous side-effects. Clearly, there is a great need for novel, potent analgesic drugs with improved safety and tolerability. The discovery of temperature-sensitive TRP channels (so-called “thermoTRP”s) in nociceptive neurons has spawned extensive research efforts to understand the role of these channels in the initiation and maintenance of pain conditions and to identify potent and selective small molecule antagonists that can be exploited for therapeutic purposes. Since these channels are strategically located at the periphery where the pain pathway begins, it is hoped that TRP antagonists will be devoid of the sideeffects that plague the clinical use of centrally-acting analgesic agents. Of note, the expression of thermoTRP channels is not restricted to nociceptive neurons. Indeed, there is good evidence that the therapeutic potential of thermoTRP blockers extend beyond pain and include airway disorders (e.g. chronic cough, asthma and chronic obstructive pulmonary disease), overactive bladder, skin diseases (e.g. skin-derived pruritus, acne and alopecia or hirsutism), and cancer, just to name a few examples. Of TRP channels that are present in nociceptive neurons, the vanilloid (capsaicin) receptor TRPV1 has attracted the most attention so far partly due to the well-documented clinical potential of capsaicin to relieve pain. This explains the focus of this special issue on TRPV1. Desensitization to capsaicin is a unique approach to lasting pain relief. After an initial excitatory response (that can be minimized by topical analgesic agents like lidocaine), TRPV1-expressing neurons develop a long-lasting (weeks in animal experiments and several months in clinical studies) refractory state in which the neurons are silent regardless of the nature of the noxious stimulus. This is important since capsaicin-sensitive neurons express a broad range of channels that are involved in pain perception. Importantly, all of these channels are silent during capsaicin desensitization....

Following the cloning and characterization of the transient receptor potential vanilloid 1 (TRPV1), a growing body of research has identified the important role of TRPV1 and related channels in diverse physiological functions including temperature transduction and pain signalling. As a result, there has been a great deal of interest by the pharmaceutical industry to develop small molecule modulators of the activity of these channels for potential therapeutic use. While most of the efforts have focused on examining the role of TRPV1 in nociception, more recent work has begun to assess the therapeutic utility of targeting other TRP channels. This manuscript is aimed at introducing the reader of this special issue to the promising new developments and findings as well as emerging challenges in the targeting of the thermoTRP family of receptors for clinical therapeutic use. This chapter will focus on current efforts from the pharmaceutical industry to develop highly potent and efficacious compounds that modulate TRP channel function. In particular, this chapter will highlight recent drug discovery activities around the transient receptor potential vanilloid family members TRPV1, TRPV3, and TRPV4, the transient receptor potential ankyrin family member TRPA1, and the transient receptor potential melastatin family member TRPM8. The majority of the work included in this chapter will focus on recent findings in the development of TRP modulators for pain indications; however, for certain targets where data exist, other indications will be discussed. The increasing number of small biotech and pharmaceutical companies pursuing targets in these families of ion channels highlights the perceived importance of these targets in the treatment of a variety of disease states including inflammatory and neuropathic pain, urinary incontinence, painful bladder syndrome, and even types of prostate cancer.

Transient Receptor Potential (TRP) cation channels participate in several processes of vital importance in cell and organism physiology, and have been demonstrated to participate in the detection of sensory stimuli. The thermo TRP's reviewed: TRPV1 (vanilloid 1), TRPM8 (melastatin 8) and TRPA1 (ankyrin-like 1) are known to integrate different chemical and physical stimuli such as changes in temperature and sensing different irritant or pungent compounds. However, despite the physiological importance of these channels the mechanisms by which they detect incoming stimuli, how the sensing domains are coupled to channel gating and how these processes are connected to specific structural regions in the channel are not fully understood, but valuable information is available. Many sites involved in agonist detection have been characterized and gating models that describe many features of the channel's behavior have been put forward. In this review we will survey some of the key findings concerning the structural and molecular mechanisms of TRPV1, TRPA1 and TRPM8 activation.

TRPV1 has emerged as a promising therapeutic target for pain as well as a broad range of other conditions such as asthma or urge incontinence. The identification of resiniferatoxin as an ultrapotent ligand partially able to dissect the acute activation of TRPV1 from subsequent desensitization and the subsequent intense efforts in medicinal chemistry have revealed that TRPV1 affords a dramatic landscape of opportunities for pharmacological manipulation. While agonism and antagonism have represented the primary directions for drug development, the pharmacological complexity of TRPV1 affords additional opportunities. Partial agonism/partial antagonism, its modulation by signaling pathways, variable desensitization, and slow kinetics of action can all be exploited through drug design.

In primary sensory neurons, the capsaicin receptor TRPV1 functions as a molecular integrator for a broad range of seemingly unrelated chemical and physical noxious stimuli, including heat and altered pH. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and tissue injury as this response is impaired in TRPV1-deficient mice. Following the molecular cloning of TRPV1 in 1997, over a dozen companies embarked on efforts to find clinically useful TRPV1 antagonists, but side-effects and limited efficacy have thus far prevented any compounds from progressing beyond phase II. This has rekindled interest in desensitization of nociceptive neurons to TRPV1 agonists (e.g. capsaicin and its ultrapotent analog resiniferatoxin) as an alternative pharmacological approach to block pain in the periphery where it is generated. The clinical value of capsaicin is, however, limited by its unfavorable irritancy to desensitization ratio. In animal experiments, resiniferatoxin treatment is a powerful approach to achieve longlasting analgesia. In patients with overactive bladder, intravesical resiniferatoxin improves bladder function (or even restores continence) without significant irritancy and/or toxicity. In this review, we argue that resiniferatoxin is an attractive alternative to capsaicin in that it achieves lasting desensitization without the side effects that complicate capsaicin therapy.

The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 acts as an important signal integrator in sensory nociceptors under physiological and pathological conditions including inflammation and neuropathy. Because of its integrative signaling properties in response to inflammatory stimuli, TRPV1 agonists and antagonists are predicted to inhibit the sensation of ongoing or burning pain that is reported by patients suffering from chronic pain, therefore offering an unprecedented advantage in selectively inhibiting painful signaling from where it is initiated. In this article, we summarize recent advances in the understanding of the role of TRPV1 in pain signaling, including an overview of clinical pharmacological trials using TRPV1 agonists and antagonists. Finally, we also present an update on the mechanistic understanding and controlling of hyperthermia caused by TRPV1 antagonists, and provide perspectives for future studies.

The transient receptor potential vanilloid 1(TRPV1) channel has been a topic of great interest, since its discovery in 1997. It is a homotetrameric non-selective cation channel predominantly expressed in a population of sensory neurons and its involvement in different modalities of pain has been extensively studied. However, TRPV1 has also been shown to be expressed in non-sensory neurons and non-neuronal cells. TRPV1 is considered as a potential target for drug development, based on its tissue distribution and its role in physiological functions. Here, we summarize the evidences for disease-related alterations in TRPV1 expression and function and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the treatment of a wide range of diseases.

The vanilloid subfamily of transient receptor potential (TRPV) ion channels serves critical functions in sensory signaling in specialized cells and intact organisms ranging from yeast to primates. As thermosensors, chemosensors, and/or mechanosensors, these channels monitor the local environment and integrate and respond to multiple stimuli distinctively. More than a decade of research on the founding member of the subclass, TRPV1, has led to advancement of multiple antagonists into the clinic for the treatment of chronic pain. In recent years the comprehensive knowledge accessed through these studies has been applied to enhance understanding of other TRPV isoforms and, in particular, to determine whether they, too, represent promising targets for drug discovery. This review focuses on emerging data that define a role for TRPV3 in transducing signals in pain pathways and identify antagonists that demonstrate efficacy in relevant preclinical behavioral models.

TRPV4 belongs to the TRPV subfamily of Transient Receptor Potential (TRP) ion channels. This year marks the 10 year anniversary of the discovery of this polymodal ion channel which is activated by a variety of stimuli including warm temperatures, hypotonicity and endogenous lipids. Coupled with a widespread tissue distribution, this activation profile has resulted in a large number of disparate physiological functions for TRPV4. These range from temperature monitoring in skin keratinocytes to osmolarity sensing in kidneys, sheer stress detection in blood vessels and osteoclast differentiation control in bone. As knowledge of its physiological roles has expanded, interest in targeting TRPV4 modulation for therapeutic purposes has arisen and is now focused on several areas. First, as with related TRP channels TRPV1, TRPV3, TRPM8 and TRPA1, TRPV4 antagonism is being considered for inflammatory and neuropathic pain treatment. Recent work conducted using KO mice and agonists 4αPDD and GSK1016790A suggests bladder dysfunctions may also be targeted. Additionally, ventilator-induced lung injury has emerged as another potential indication for TRPV4 antagonists. Herein we review the known small molecule modulators of TRPV4 and relate progress made in identifying potent, selective and bioavailable agonists and antagonists to interrogate this ion channel in vivo.

TRPA1 is a member of a superfamily of non-selective cation channels that is known to be involved in multiple physiological functions. TRPA1 is activated by a broad spectrum of chemical irritants and endogenous inflammatory compounds. An emerging role for TRPA1 in mediating pain and inflammation raises the possibility that compounds targeting TRPA1 might have significant therapeutic potential. This review discusses the broad classes of molecules that are known to act as agonists and antagonists of TRPA1 towards the aim of providing an overview of the structure and activity of TRPA1 modulators.

TRPM8 belongs to the TRPM Melastatin subfamily of Transient Receptor Potential (TRP) ion channels. Activated by cool temperatures and mimetic ligands, such as menthol and icilin, TRPM8 has been shown to play a role in thermoreception and is expressed in peripheral nerves. TRPM8 is also expressed in other tissues which are not exposed to temperature fluctuations, such as the prostate. The recent advancement of a TRPM8 agonist into the clinic for the treatment of prostate cancer suggests that the channel plays a role in some human pathologies. As more drug-like and selective agonists and antagonists of TRPM8 become available, in vivo pharmacology studies will complement already published knockout data to further our understanding of the role of TRPM8 in human disease.

Release of somatostatin into the circulation from the activated TRPV1-expressing nociceptors revealed by antidromic stimulation of dorsal roots in the rat pinpointed to a novel potential drug target on these nociceptors. The review summarizes the functional, biochemical and pharmacological evidence for a novel somatostatin-mediated counterregulatory antiinflammatory/antinociceptive “sensocrine” function in rats and guinea-pigs. To identify the somatostatin receptor subtype(s) responsible for this function, experiments were focused on actions of sstR4 receptor agonists as this subtype, similarly to sstR1, is not involved in endocrine regulation. Involvement of somatostatin and the sstR4 was revealed by using pretreatment with somatostatin antibody, depletion of somatostatin with cysteamine, measuring the plasma somatostatin-like immunoreactivity, release from nerves in vitro of the isolated trachea, detection of sstR4 receptors in animal and human tissue specimens, using sstR4 gene-deleted mice and investigating in the detail effects of a stable peptide analogue of somatostatin (TT-232) and an ultrapotent non-peptide agonist of sstR4 receptors. Promising antinociceptive, antihyperalgesic effects of these sstR4 agonists were observed in various experimental models of inflammatory and neuropathic conditions which are mediated both by TRPV1-expressing nociceptors and non-neural cells involved in mediation of inflammation. In sstR4 receptor knockout mice an aggravation of inflammation and hyperalgesia was observed.