TRP channels as therapeutic targets in airway disorders: a patent review

INTRODUCTION: Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease, affect millions of patients worldwide. New therapeutic approaches to these conditions are urgently needed since current treatment options provide only symptomatic relief. Transient receptor potential (TRP) ion channels are emerging molecular target candidates for the development of novel, disease-modifying drugs addressing airway diseases. AREAS COVERED: The authors review the patent literature on novel molecules targeting TRP channels (in particular TRPA1, TRPV1, TRPM8 and TRPC6) that are currently studied in clinical trials or are candidates for future clinical evaluation in the management of respiratory diseases. EXPERT OPINION: The patent literature highlights TRPA1 and TRPV1 channels as the most advanced therapeutic targets in respiratory disorders. TRPV1 antagonists relieve cough in preclinical studies. TRPA1 antagonists not only are anti-tussive but also show efficacy in allergic asthma models. However, to date, only minimal clinical data are available regarding the effects of selective, small-molecule TRPV1 and TRPA1 blockers in respiratory disorders. Clearly, long-term clinical studies are required to confirm the expectations based on preclinical data. In conclusion, the current status of this rapidly expanding research area raises cautious optimism for TRPA1 (and possibly also TRPV1) antagonists as promising anti-tussive/anti-asthma drug candidates.     

Agents in early development for treatment of bladder dysfunction – promise of drugs acting at TRP channels?

Introduction: In the lower urinary tract (LUT) several members of the TRP superfamily are involved in nociception and mechanosensory transduction. Animal studies have suggested a therapeutic potential of some of these channels, including TRPV1, TRPV4, TRPM8, TRPA1, and TRPM4, for treatment of bladder over- and underactivity and bladder pain disorders, but translation of this information to clinical application has been slow.

Areas covered: An update on and discussion of current information on the potential clinical use of TRP channel agonists/antagonists in the treatment of different types of bladder dysfunction. The electronic databases PubMed and Scopus were used to identify relevant clinical and animal studies.

Expert opinion: The therapeutic effect of TRPV1 channel desensitizing agonists (capsaicin, resiniferatoxin, given intravesically) has been convincingly demonstrated in some forms of bladder overactivity. However, so far, the potential of any of the small-molecule TRP channel blockers developed for non-bladder indications and tested in early human trials for safety has not been explored clinically in LUT dysfunction. The adverse effects of hyperthermia and reduction of noxious heat sensation of the first generation TRPV1 blockers have delayed development. Despite lack of translational information, TRP channels remain interesting targets for future LUT drugs.     

TRP Channels in Respiratory Pathophysiology: The Role of Oxidative,Chemical Irritant and Temperature Stimuli

There is rapidly growing evidence indicating multiple and important roles of Ca²⁺-permeable cation TRP channels in the airways, both under normal and disease conditions. The aim of this review was to summarize the current knowledge of TRP channels in sensing oxidative, chemical irritant and temperature stimuli by discussing expression and function of several TRP channels in relevant cell types within the respiratory tract, ranging from sensory neurons to airway smooth muscle and epithelial cells. Several of these channels, such as TRPM2, TRPM8, TRPA1 and TRPV1, are discussed in much detail to show that they perform diverse, and often overlapping or contributory, roles in airway hyperreactivity, inflammation, asthma, chronic obstructive pulmonary disease and other respiratory disorders. These include TRPM2 involvement in the disruption of the bronchial epithelial tight junctions during oxidative stress, important roles of TRPA1 and TRPV1 channels in airway inflammation, hyperresponsiveness, chronic cough, and hyperplasia of airway smooth muscles, as well as TRPM8 role in COPD and mucus hypersecretion. Thus, there is increasing evidence that TRP channels not only function as an integral part of the important endogenous protective mechanisms of the respiratory tract capable of detecting and ensuring proper physiological responses to various oxidative, chemical irritant and temperature stimuli, but that altered expression, activation and regulation of these channels may also contribute to the pathogenesis of respiratory diseases.     

Transient receptor potential (TRP) channels: a clinical perspective

Transient receptor potential (TRP) channels are important mediators of sensory signals with marked effects on cellular functions and signalling pathways. Indeed, mutations in genes encoding TRP channels are the cause of several inherited diseases in humans (the so-called ‘TRP channelopathies’) that affect the cardiovascular, renal, skeletal and nervous systems. TRP channels are also promising targets for drug discovery. The initial focus of research was on TRP channels that are expressed on nociceptive neurons. Indeed, a number of potent, small-molecule TRPV1, TRPV3 and TRPA1 antagonists have already entered clinical trials as novel analgesic agents. There has been a recent upsurge in the amount of work that expands TRP channel drug discovery efforts into new disease areas such as asthma, cancer, anxiety, cardiac hypertrophy, as well as obesity and metabolic disorders. A better understanding of TRP channel functions in health and disease should lead to the discovery of first-in-class drugs for these intractable diseases. With this review, we hope to capture the current state of this rapidly expanding and changing field.

LINKED ARTICLES

This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10     

TRP channels as emerging targets for pain therapeutics

Background: The transient receptor potential (TRP) superfamily of ion channels are a large and diverse group that have received increased attention in recent years. The sub-family of thermo-TRPs which are regulated by temperature, among other physical and chemical stimuli, are of particular interest for the development of potential pain therapeutics. Objective/methods: We review the advances in the field in recent years, focusing on a rationale for pain therapy and potential challenges associated with these targets. Results/conclusions: Vanilloid-type TRP 1 (TRPV1) is the most well studied and advanced member of the family, with selective agonists and antagonists already in clinical use or development, respectively. Among other thermo-TRPs (including TRPV2 – 4, Ankyrin type TRP 1 (TRPA1) and melastatin type TRP 8 (TRPM8)), TRPA1 and TRPM8 are emerging as promising novel pain targets.     

化疗引起的神经痛治疗靶点温度选择性TRP通道的研究进展

作为钙离子渗透性的瞬时受体电位(TRP),5种通道(TRPV1~4和TRPM2)被不同的高温激活,两种通道(TRPV1和TRPV8)被低温激活。越来越多的证据表明,TRPA1和TRPM8拮抗剂可预防顺铂、奥沙利铂和紫杉醇诱导的线粒体氧化应激、炎症、冷痛和痛觉过敏。TRPV1在顺铂引起的感觉神经元热痛觉和机械异常中有应答。TRPA1、TRPM8和TRPV2蛋白表达水平主要通过这些治疗方法在背根(DRG)和三叉神经节中增加。主要总结了5种温度调节TRP通道(TRPA1、TRPM8、TRPV1、TRPV2和TRPV4)。     

Transient receptor potential ion channels as targets for the discovery of pain therapeutics

A subset of transient receptor potential (TRP) channels exhibits activity that is highly sensitive to temperature changes and is expressed in sensory tissues, such as nociceptors and skin. Some of these thermosensitive TRP channels, such as TRPV1, TRPV4 and TRPA1, are activated or sensitized by molecules generated by inflammation and/or cell damage. TRPV1, also known as the capsaicin receptor, is particularly important in mediating hyperalgesic responses in inflammatory pain states, as demonstrated by research in knockout animals and with small-molecule antagonists. It is anticipated that TRPV1 antagonists, and perhaps antagonists at other thermosensitive TRP channels, will provide new therapeutic options with which to treat clinical pain.     

Identification of herbal components as TRPA1 agonists and TRPM8 antagonists

Transient receptor potential (TRP) channels are non-selective cation channels that are implicated in analgesia, bowel motility, wound healing, thermoregulation, vasodilation and voiding dysfunction. Many natural products have been reported to affect the activity of TRP channels. We hypothesize that numerous traditional herbal medicines (THMs) might exert their pharmacological activity through modulating the activity of TRP channels. The present study aimed to evaluate the effects of flavonoid aglycones and their glycosides, which are the main components of many THMs, on the TRP channel subtypes. A Ca²⁺ influx assay was performed using recombinant human TRPA1, TRPV1, TRPV4 and TRPM8 cell lines. Our findings showed that flavonoid aglycones and glycycoumarin activated TRPA1. In particular, isoflavone and chalcone compounds displayed potent TRPA1 agonistic activity. Furthermore, flavone aglycones showed concomitant potent TRPM8 inhibiting activity. Indeed, flavone, isoflavone aglycones, non-prenylated chalcones and glycycoumarin were found to be TRPM8 inhibitors. Hence, flavonoid aglycones metabolized by lactase-phlorizin hydrolase and β-glucosidase in the small intestine or gut microbiota of the large intestine could generate TRPA1 agonists and TRPM8 antagonists.

     

Activation of transient receptor potential A1 by a non-pungent capsaicin-like compound, capsiate

BACKGROUND AND PURPOSE

Capsiate is produced by ‘CH-19 Sweet’ (Capsicum annuun L.), a non-pungent cultivar of red pepper. Like capsaicin, capsiate is thought to enhance energy metabolism by activating the sympathetic nervous system and suppressing inflammation, but the underlying mechanisms for this are uncertain. We previously reported that capsiate could activate transient receptor potential vanilloid 1 (TRPV1), a capsaicin receptor. The purpose of the present study is to investigate whether capsinoids activate other TRP channels.

EXPERIMENTAL APPROACH

Using Ca²⁺ imaging and whole-cell patch-clamp methods, we analysed the response of TRP channels to three kinds of capsinoids, capsiate, dihydrocapsiate and nordihydrocapsiate, in HEK293T cells expressing TRP channels or in primary cultures of mouse dorsal root ganglion neurons.

KEY RESULTS

We found that in both cell types TRP ankyrin 1 (TRPA1) had a slightly weaker response to capsinoids compared with TRPV1, with the capsiate EC₅₀ for TRPA1 activation being more than that for TRPV1 activation, and that the capsinoid-evoked action was blocked by a specific TRPA1 antagonist. TRPA1 was activated by capsinoids, but not by their degradation products. Amino acids known to participate in TRPA1 activation following cysteine covalent modification or zinc treatment were not involved in the activation of TRPA1 by capsinoid.

CONCLUSIONS AND IMPLICATIONS

Taken together, these results indicate that capsinoids activate TRPA1 by an as yet unknown mechanism, and TRPA1 could be involved in physiological phenomena associated with capsinoid treatment.     

The functions of TRPA1 and TRPV1: moving away from sensory nerves

The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation.     

The thermo-TRP ion channel family: properties and therapeutic implications

The thermo-transient receptor potentials (TRPs), a recently discovered family of ion channels activated by temperature, are expressed in primary sensory nerve terminals where they provide information about thermal changes in the environment. Six thermo-TRPs have been characterised to date: TRP vanilloid (TRPV) 1 and 2 are activated by painful levels of heat, TRPV3 and 4 respond to non-painful warmth, TRP melastatin 8 is activated by non-painful cool temperatures, while TRP ankyrin (TRPA) 1 is activated by painful cold. The thermal thresholds of many thermo-TRPs are known to be modulated by extracellular mediators, released by tissue damage or inflammation, such as bradykinin, PG and growth factors. There have been intensive efforts recently to develop antagonists of thermo-TRP channels, particularly of the noxious thermal sensors TRPV1 and TRPA1. Blockers of these channels are likely to have therapeutic uses as novel analgesics, but may also cause unacceptable side effects. Controlling the modulation of thermo-TRPs by inflammatory mediators may be a useful alternative strategy in developing novel analgesics.     

Transient receptor potential vanilloid-1 antagonists: a survey of recent patent literature

Importance of the field: Transient receptor potential vanilloid-1 (TRPV1, vanilloid receptor-1) is a nonspecific cation channel that can be activated by multiple endogenous stimuli and by capsaicin, the active ingredient in chili peppers. TRPV1 is expressed predominantly on sensory neurons where it is proposed to serve as a key nodal point in pain transmission pathways. Pharmacological blockade of TRPV1 represents a compelling strategy for the treatment of a variety of disease states, particularly those requiring chronic pain management.

Area covered in the review: This review summarizes patent literature and progress in defining the utility of small molecule TRPV1 antagonists during 2008 – 2009.

What the reader will gain: Representative compounds and key characterization data comprising multiple chemical series are highlighted.

Take home message: The continued profusion of reports, in both the primary and patent literature, attests to the sustained interest in the TRPV1 class of therapeutics. Although a number of compounds have now been brought forward for human clinical trials, the therapeutic utility of TRPV1 antagonists is yet to be validated unequivocally.     

Transient receptor potential (TRP) channels in the airway: role in airway disease

Over the last few decades, there has been an explosion of scientific publications reporting the many and varied roles of transient receptor potential (TRP) ion channels in physiological and pathological systems throughout the body. The aim of this review is to summarize the existing literature on the role of TRP channels in the lungs and discuss what is known about their function under normal and diseased conditions. The review will focus mainly on the pathogenesis and symptoms of asthma and chronic obstructive pulmonary disease and the role of four members of the TRP family: TRPA1, TRPV1, TRPV4 and TRPM8. We hope that the article will help the reader understand the role of TRP channels in the normal airway and how their function may be changed in the context of respiratory disease.     

Activation of the Chemosensory Ion Channels TRPA1 and TRPV1 by Hydroalcohol Extract of Kalopanax pictus Leaves

TRPA1 and TRPV1 are members of the TRP superfamily of structurally related, nonselective cation channels. TRPA1 and TRPV1 are often co-expressed in sensory neurons and play an important role in somatosense such as cold, pain, and irritants. The first leaves of Kalopanax pictus Nakai (Araliaceae) have long been used as a culinary ingredient in Korea because of their unique chemesthetic flavor. In this study, we observed the intracellular Ca²⁺ response to cultured cells expressing human TRPA1 (hTRPA1) and human TRPV1 (hTRPV1) by Ca²⁺ imaging analysis to investigate the ability of the first leaves of K. pictus to activate the hTRPA1 and hTRPV1. An 80% ethanol extract of K. pictus (KPEx) increased intracellular Ca²⁺ influx in a response time- and concentration-dependent manner via either hTRPA1 or hTRPV1. KPEx-induced response to hTRPA1 was markedly attenuated by ruthenium red, a general blocker of TRP channels, and HC-030031, a specific antagonist of TRPA1. In addition, the intracellular Ca²⁺ influx attained with KPEx to hTRPV1 was mostly blocked by ruthenium red, and capsazepine, a specific antagonist of TRPV1. These results indicate that KPEx selectively activates both hTRPA1 and hTRPV1, which may provide evidence that the first leaves of K. pictus primarily activate TRPA1 and TRPV1 to induce their unique chemesthetic sense.     

Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents

Background and purpose:

The transient receptor potential ankyrin receptor 1 (TRPA1) is a cation channel, co-expressed with the pro-tussive transient receptor potential vanilloid type 1 (TRPV1) channel in primary sensory neurons. TRPA1 is activated by a series of irritant exogenous and endogenous α,β-unsaturated aldehydes which seem to play a role in airway diseases. We investigated whether TRPA1 agonists provoke cough in guinea pigs and whether TRPA1 antagonists inhibit this response.

Experimental approach:

Animals were placed in a Perspex box, and cough sounds were recorded and counted by observers unaware of the treatment used.

Key results:

Inhalation of two selective TRPA1 agonists, allyl isothiocyanate and cinnamaldehyde, dose-dependently caused cough in control guinea pigs, but not in those with airway sensory nerves desensitized by capsaicin. Coughs elicited by TRPA1 agonists were reduced by non-selective (camphor and gentamicin) and selective (HC-030031) TRPA1 antagonists, whereas they were unaffected by the TRPV1 antagonist, capsazepine. Acrolein and crotonaldehyde, two α,β-unsaturated aldehydes recently identified as TRPA1 stimulants and contained in cigarette smoke, air pollution or produced endogenously by oxidative stress, caused a remarkable tussive effect, a response that was selectively inhibited by HC-030031. Part of the cough response induced by cigarette smoke inhalation was inhibited by HC-030031, suggesting the involvement of TRPA1.

Conclusions and implications:

A novel pro-tussive pathway involves the TRPA1 channel, expressed by capsaicin-sensitive airway sensory nerves and is activated by a series of exogenous (cigarette smoke) and endogenous irritants. These results suggest TRPA1 may be a novel target for anti-tussive medicines.     

TRP channels in neurogastroenterology: opportunities for therapeutic intervention

The members of the superfamily of transient receptor potential (TRP) cation channels are involved in a plethora of cellular functions. During the last decade, a vast amount of evidence is accumulating that attributes an important role to these cation channels in different regulatory aspects of the alimentary tract. In this review we discuss the expression patterns and roles of TRP channels in the regulation of gastrointestinal motility, enteric nervous system signalling and visceral sensation, and provide our perspectives on pharmacological targeting of TRPs as a strategy to treat various gastrointestinal disorders. We found that the current knowledge about the role of some members of the TRP superfamily in neurogastroenterology is rather limited, whereas the function of other TRP channels, especially of those implicated in smooth muscle cell contractility (TRPC4, TRPC6), visceral sensitivity and hypersensitivity (TRPV1, TRPV4, TRPA1), tends to be well established. Compared with expression data, mechanistic information about TRP channels in intestinal pacemaking (TRPC4, TRPC6, TRPM7), enteric nervous system signalling (TRPCs) and enteroendocrine cells (TRPM5) is lacking. It is clear that several different TRP channels play important roles in the cellular apparatus that controls gastrointestinal function. They are involved in the regulation of gastrointestinal motility and absorption, visceral sensation and visceral hypersensitivity. TRP channels can be considered as interesting targets to tackle digestive diseases, motility disorders and visceral pain. At present, TRPV1 antagonists are under development for the treatment of heartburn and visceral hypersensitivity, but interference with other TRP channels is also tempting. However, their role in gastrointestinal pathophysiology first needs to be further elucidated.     

Expression of multiple Transient Receptor Potential channel genes in murine 3T3-L1 cell lines and adipose tissue

BackgroundCalcium and its signaling have a role in adipogenesis. Transient Receptor Potential (TRP) channels are non-selective cation channels with a high permeability to calcium.MethodsIn the present study the expression of multiple TRP channels on mouse 3T3-L1 preadipocyte and adipocyte cells, white (WAT) and brown (BAT) adipose tissues was investigated using real time PCR (RT-PCR).ResultsTRPV1, TRPV3, TRPM8, TRPC4, TRPC6 were differentially expressed in preadipocytes and adipocytes suggesting their significance in adipogenesis. Genes for multiple TRP channels were also expressed in murineWAT and BAT, out of which TRPV4, TRPV6 and TRPC6 showed differential expression.ConclusionPresent study demonstrates the expression of TRP channels in mouse cell lines and adipose tissues.     

Pain transduction: a pharmacologic perspective

Introduction: Pain represents a necessary physiological function yet remains a significant pathological process in humans across the world. The transduction of a nociceptive stimulus refers to the processes that turn a noxious stimulus into a transmissible neurological signal. This involves a number of ion channels that facilitate the conversion of nociceptive stimulus into and electrical signal.

Areas covered: An understanding of nociceptive physiology complements a discussion of analgesic pharmacology. Therefore, the two are presented together. In this review article, a critical evaluation is provided on research findings relating to both the physiology and pharmacology of relevant acid-sensing ion channels (ASICs), transient receptor potential (TRP) cation channels, and voltage-gated sodium (Nav) channels.

Expert commentary: Despite significant steps toward identifying new and more effective modalities to treat pain, there remain many avenues of inquiry related to pain transduction. The activity of ASICs in nociception has been demonstrated but the physiology is not fully understood. A number of medications appear to interact with ASICs but no research has demonstrated pain-relieving clinical utility. Direct antagonism of TRPV1 channels is not in practice due to concerning side effects. However, work in this area is ongoing. Additional research in the of TRPA1, TRPV3, and TRPM8 may yield useful results. Local anesthetics are widely used. However, the risk for systemic effects limits the maximal safe dosage. Selective Nav antagonists have been identified that lack systemic effects.     

The TRPA1 channel in migraine mechanism and treatment

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment.

Linked Articles

This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10     

Compounds from Sichuan and Melegueta peppers activate,covalently and non-covalently,TRPA1 and TRPV1 channels

Background and purpose:

Oily extracts of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-α-sanshool (α-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations.

Experimental approach:

The structure–activity relationships of these molecules on TRPA1 and TRPV1 was measured by testing natural and synthetic analogues using calcium and voltage imaging on dissociated dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addition, using Trpv1 knockout mice, the compounds'' aversive responses were measured in a taste brief-access test.

Key results:

For TRPA1 activation, the cis C6 double bond in the polyenic chain of α-SOH was critical, whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compounds activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to α-SOH.

Conclusions and implications:

The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compounds.