Special Issue "Transient Receptor Potential (TRP) Channels in Drug Discovery: Unlocking the Potential"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (28 February 2019)

Special Issue Editors

Guest Editor
Dr. Arpad Szallasi

Semmelweis University, Budapest, Hungary; and PILA PHARMA, Malmö, Sweden
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Interests: role of TRP channels in health and disease
Guest Editor
Dr. Sonya Lehto

Amgen, CA, USA
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Special Issue Information

Dear Colleagues,

The molecular cloning of TRPV1 in 1997 opened up a new chapter in drug discovery efforts. According to PubMed, during the past five years more than one TRPV1 paper has been published every day (adding up to a total of 2,565), and the postulated role of TRPV1 now goes well-beyond traditional indications like chronic pain to include obesity/metabolic disorders, hypertension, cancer, or even fertility and psychiatric disorders.

An unprecedented investment by pharma into the development of TRPV1 antagonists ushered compounds into clinical trials with record speed where most flamed out due to a combination of unforeseen side-effects (most important, hyperthermia and compromised heat pain sensation) and a lack of clinical efficacy. However, with the decline of TRPV1, other TRP channels have emerged as promising therapeutic targets. At present, TRPA1, TRPV3 and V4, and TRPM8 are being tested in patients, but other TRP channels like TRPC4/C5 are probably not far behind.

In 2016, the journal Pharmaceuticals published a well-received, but admittedly incomplete collection of reviews on TRP channels as therapeutic targets (“old thoughts, new concepts”) which is now also available as an eBook. Now we invite both review articles and originals findings to be included in Volume 2 (“unlocking the potential”). Like Volume 1, this collection of manuscripts will be published first as a Special Issue in the journal, and hopefully later as an eBook. Please, email either Sonya Lehto or Arpad Szallasi if you would like to contribute a paper to this TRP channel issue.

Link for the first issue:https://www.mdpi.com/journal/pharmaceuticals/special_issues/old_concepts_new_thoughts  

Dr. Arpad Szallasi
Dr. Sonya Lehto
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 850 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TRP channels
  • mavatrep
  • lung disease
  • dry eye
  • IBD
  • migraine
  • urinary incontinence
  • thermoregulatory grooming

Published Papers (9 papers)

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Research

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Open AccessArticle Camphor, Applied Epidermally to the Back, Causes Snout- and Chest-Grooming in Rats: A Response Mediated by Cutaneous TRP Channels
Pharmaceuticals 2019, 12(1), 24; https://doi.org/10.3390/ph12010024
Received: 1 December 2018 / Revised: 21 January 2019 / Accepted: 31 January 2019 / Published: 2 February 2019
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Abstract
Thermoregulatory grooming, a behavioral defense against heat, is known to be driven by skin-temperature signals. Because at least some thermal cutaneous signals that drive heat defenses are likely to be generated by transient receptor potential (TRP) channels, we hypothesized that warmth-sensitive TRPs drive [...] Read more.
Thermoregulatory grooming, a behavioral defense against heat, is known to be driven by skin-temperature signals. Because at least some thermal cutaneous signals that drive heat defenses are likely to be generated by transient receptor potential (TRP) channels, we hypothesized that warmth-sensitive TRPs drive thermoregulatory grooming. Adult male Wistar rats were used. We showed that camphor, a nonselective agonist of several TRP channels, including vanilloid (V) 3, when applied epidermally to the back (500 mg/kg), caused a pronounced self-grooming response, including paw-licking and snout- and chest-“washing”. By the percentage of time spent grooming, the response was similar to the thermoregulatory grooming observed during exposure to ambient warmth (32 °C). Ruthenium red (a non-selective antagonist of TRP channels, including TRPV3), when administered intravenously at a dose of 0.1 mg/kg, attenuated the self-grooming behavior induced by either ambient warmth or epidermal camphor. Furthermore, the intravenous administration of AMG8432 (40 mg/kg), a relatively selective TRPV3 antagonist, also attenuated the self-grooming response to epidermal camphor. We conclude that camphor causes the self-grooming behavior by acting on TRP channels in the skin. We propose that cutaneous warmth signals mediated by TRP channels, possibly including TRPV3, drive thermoregulatory self-grooming in rats. Full article
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Open AccessArticle TRPV1 Inhibits the Ventilatory Response to Hypoxia in Adult Rats, but Not the CO2-Drive to Breathe
Pharmaceuticals 2019, 12(1), 19; https://doi.org/10.3390/ph12010019
Received: 25 October 2018 / Revised: 27 November 2018 / Accepted: 7 December 2018 / Published: 24 January 2019
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Abstract
Receptors of the transient receptor potential (TRP) channels superfamily are expressed in many tissues and have different physiological functions. However, there are few studies investigating the role of these channels in cardiorespiratory control in mammals. We assessed the role of central and peripheral [...] Read more.
Receptors of the transient receptor potential (TRP) channels superfamily are expressed in many tissues and have different physiological functions. However, there are few studies investigating the role of these channels in cardiorespiratory control in mammals. We assessed the role of central and peripheral TRPV1 receptors in the cardiorespiratory responses to hypoxia (10% O2) and hypercapnia (7% CO2) by measuring pulmonary ventilation ( V ˙ E ), heart rate (HR), mean arterial pressure (MAP) and body temperature (Tb) of male Wistar rats before and after intraperitoneal (AMG9810 [2.85 µg/kg, 1 mL/kg]) or intracebroventricular (AMG9810 [2.85 µg/kg, 1 µL] or AMG7905 [28.5 μg/kg, 1 µL]) injections of TRPV1 antagonists. Central or peripheral injection of TRPV1 antagonists did not change cardiorespiratory parameters or Tb during room air and hypercapnic conditions. However, the hypoxic ventilatory response was exaggerated by both central and peripheral injection of AMG9810. In addition, the peripheral antagonist blunted the drop in Tb induced by hypoxia. Therefore, the current data provide evidence that TRPV1 channels exert an inhibitory modulation on the hypoxic drive to breathe and stimulate the Tb reduction during hypoxia. Full article
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Review

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Open AccessReview TRP Channels and Migraine: Recent Developments and New Therapeutic Opportunities
Pharmaceuticals 2019, 12(2), 54; https://doi.org/10.3390/ph12020054
Received: 1 March 2019 / Revised: 1 April 2019 / Accepted: 4 April 2019 / Published: 9 April 2019
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Abstract
Migraine is the second-most disabling disease worldwide, and the second most common neurological disorder. Attacks can last many hours or days, and consist of multiple symptoms including headache, nausea, vomiting, hypersensitivity to stimuli such as light and sound, and in some cases, an [...] Read more.
Migraine is the second-most disabling disease worldwide, and the second most common neurological disorder. Attacks can last many hours or days, and consist of multiple symptoms including headache, nausea, vomiting, hypersensitivity to stimuli such as light and sound, and in some cases, an aura is present. Mechanisms contributing to migraine are still poorly understood. However, transient receptor potential (TRP) channels have been repeatedly linked to the disorder, including TRPV1, TRPV4, TRPM8, and TRPA1, based on their activation by pathological stimuli related to attacks, or their modulation by drugs/natural products known to be efficacious for migraine. This review will provide a brief overview of migraine, including current therapeutics and the link to calcitonin gene-related peptide (CGRP), a neuropeptide strongly implicated in migraine pathophysiology. Discussion will then focus on recent developments in preclinical and clinical studies that implicate TRP channels in migraine pathophysiology or in the efficacy of therapeutics. Given the use of onabotulinum toxin A (BoNTA) to treat chronic migraine, and its poorly understood mechanism, this review will also cover possible contributions of TRP channels to BoNTA efficacy. Discussion will conclude with remaining questions that require future work to more fully evaluate TRP channels as novel therapeutic targets for migraine. Full article
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Open AccessReview Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets?
Pharmaceuticals 2019, 12(2), 48; https://doi.org/10.3390/ph12020048
Received: 11 March 2019 / Revised: 26 March 2019 / Accepted: 27 March 2019 / Published: 30 March 2019
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Abstract
Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and [...] Read more.
Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and neurogenic inflammation. This review provides an overview of their expression and role in intestinal inflammation, in particular colitis, that appears to be virtually inconsistent based on the thorough investigations of the last twenty years. However, preclinical results with pharmacological interventions, as well as scarcely available human studies, more convincingly point out the potential therapeutic value of TRPV1 and TRPA1 antagonists in colitis and visceral hypersensitivity providing future therapeutical perspectives through a complex, unique mechanism of action for drug development in IBD. Full article
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Open AccessReview Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease
Pharmaceuticals 2019, 12(1), 23; https://doi.org/10.3390/ph12010023
Received: 15 January 2019 / Revised: 28 January 2019 / Accepted: 29 January 2019 / Published: 1 February 2019
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Abstract
The lungs are essential for gas exchange and serve as the gateways of our body to the external environment. They are easily accessible for drugs from both sides, the airways and the vasculature. Recent literature provides evidence for a role of Transient Receptor [...] Read more.
The lungs are essential for gas exchange and serve as the gateways of our body to the external environment. They are easily accessible for drugs from both sides, the airways and the vasculature. Recent literature provides evidence for a role of Transient Receptor Potential (TRP) channels as chemosensors and essential members of signal transduction cascades in stress-induced cellular responses. This review will focus on TRP channels (TRPA1, TRPC6, TRPV1, and TRPV4), predominantly expressed in non-neuronal lung tissues and their involvement in pathways associated with diseases like asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), lung fibrosis, and edema formation. Recently identified specific modulators of these channels and their potential as new therapeutic options as well as strategies for a causal treatment based on the mechanistic understanding of molecular events will also be evaluated. Full article
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Open AccessReview TRPM8 Channels and Dry Eye
Pharmaceuticals 2018, 11(4), 125; https://doi.org/10.3390/ph11040125
Received: 17 September 2018 / Revised: 5 November 2018 / Accepted: 12 November 2018 / Published: 15 November 2018
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Abstract
Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence [...] Read more.
Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist. Full article
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Open AccessReview TRPA1 Antagonists for Pain Relief
Pharmaceuticals 2018, 11(4), 117; https://doi.org/10.3390/ph11040117
Received: 1 October 2018 / Revised: 23 October 2018 / Accepted: 23 October 2018 / Published: 1 November 2018
Cited by 2 | PDF Full-text (611 KB) | HTML Full-text | XML Full-text
Abstract
Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes [...] Read more.
Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission. TRPA1 is a final common pathway for a large number of chemically diverse pronociceptive agonists generated in various pathophysiological pain conditions. Thereby, pain therapy using TRPA1 antagonists can be expected to be a superior approach when compared with many other drugs targeting single nociceptive signaling pathways. In experimental animal studies, pharmacological or genetic blocking of TRPA1 has effectively attenuated mechanical and cold pain hypersensitivity in various experimental models of pathophysiological pain, with only minor side effects, if any. TRPA1 antagonists acting peripherally are likely to be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals), while centrally acting TRPA1 antagonists are expected to be optimal for attenuating pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries). In an experimental model of peripheral diabetic neuropathy, prolonged blocking of TRPA1 has delayed the loss of nociceptive nerve endings and their function, thereby promising to provide a disease-modifying treatment. Full article
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Open AccessReview Evidence for Transient Receptor Potential (TRP) Channel Contribution to Arthritis Pain and Pathogenesis
Pharmaceuticals 2018, 11(4), 105; https://doi.org/10.3390/ph11040105
Received: 1 September 2018 / Revised: 8 October 2018 / Accepted: 12 October 2018 / Published: 15 October 2018
Cited by 2 | PDF Full-text (661 KB) | HTML Full-text | XML Full-text
Abstract
Based on clinical and preclinical evidence, Transient Receptor Potential (TRP) channels have emerged as potential drug targets for the treatment of osteoarthritis, rheumatoid arthritis, and gout. This review summarizes the relevant data supporting a role for various TRP channels in arthritis pain and [...] Read more.
Based on clinical and preclinical evidence, Transient Receptor Potential (TRP) channels have emerged as potential drug targets for the treatment of osteoarthritis, rheumatoid arthritis, and gout. This review summarizes the relevant data supporting a role for various TRP channels in arthritis pain and pathogenesis, as well as the current state of pharmacological efforts to ameliorate arthritis symptoms in patient populations. Full article
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Open AccessReview TRP Channels as Drug Targets to Relieve Itch
Pharmaceuticals 2018, 11(4), 100; https://doi.org/10.3390/ph11040100
Received: 4 September 2018 / Revised: 26 September 2018 / Accepted: 3 October 2018 / Published: 6 October 2018
Cited by 1 | PDF Full-text (540 KB) | HTML Full-text | XML Full-text
Abstract
Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch [...] Read more.
Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch at the molecular, cellular, and circuit levels. There is growing evidence that transient receptor potential (TRP) channels play important roles in itch signaling. The purpose of this review is to summarize our current knowledge about the role of TRP channels in the generation of itch under both physiological and pathological conditions, thereby identifying them as potential drug targets for effective anti-itch therapies. Full article
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