Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists

Preti, Delia; Saponaro, Giulia; Szállaśi, A

doi:10.4155/ppa.14.60

Cited by 45 publications

(42 citation statements)

References 85 publications

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“…Arguing against such a mechanism is the observation that reduced abdominal contractions were observed in mice after a single oral dose of a TRPA1 agonist. Furthermore, one TRPA1 antagonist has recently shown efficacy in patients with painful diabetic neuropathy, and several other TRPA1 antagonists have entered the phase of testing in clinical trials . Although the true potential of these drugs will need to be explored, their safety profile appears to be more favourable than that of early TRPV1 antagonists.…”

Section: Discussionmentioning

confidence: 99%

Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome

Beckers

Weerts

Helyes

et al. 2017

Aliment Pharmacol Ther

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Section: Discussionmentioning

confidence: 99%

Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome

Beckers

Weerts

Helyes

et al. 2017

Aliment Pharmacol Ther

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“…3 it is currently unclear to which extend they are functionally dependent on each other [22,70,79]. Recently, TRPA1 has been widely implicated in a number of painful and inflammatory conditions and is considered a promising potential target for the development of, amongst others, analgesic, antipruritic and anti-inflammatory pharmacotherapeutics [4,21,36,64]. For instance, the channel has been proposed to play a role in the pathoetiology of numerous disorders based on in vivo studies including neuropathic pain [9], migraine [11] and arthritis [29] and expression of the channel has been found upregulated in human tissues in conditions such as oral lichen planus [40], post-burn pruritus [85] and inflammatory bowel disorder [41] -conditions that are often associated with neuro-inflammation and pain.…”

Section: A C C E P T E Dmentioning

confidence: 99%

“…The physiological role of TRPA1 in the sensory nervous system is not only restricted to chemonociception [39,47,53,60]; the channel has also been suggested to play important roles in mediating cold pain sensation [6,23,80], pruriception [28,46,84], the cough reflex [24,64] and to act as an immunological co-activator [15,69]. The TRPA1-channel is substantially co-expressed with transient receptor potential cation channel V1 (TRPV1) on peptidergic nociceptors [34] and these frequently act in conjunction to detect numerous environmental chemical irritants although…”

Section: Introductionmentioning

confidence: 99%

Dose–response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation

Andersen¹,

Vecchio²,

Gazerani³

et al. 2017

Pain

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Despite being a ubiquitous animal pain model, the natural TRPA1-agonist allyl isothiocyanate (AITC, also known as "mustard oil") has only been sparsely investigated as a potential human surrogate model of pain, sensitization, and neurogenic inflammation. Its dose-response as an algogenic, sensitizing irritant remains to be elucidated in human skin. Three concentrations of AITC (10%, 50%, and 90%) and vehicle (paraffin) were applied for 5 minutes to 3 × 3 cm areas on the volar forearms in 14 healthy volunteers, and evoked pain intensity (visual analog scale 0-100 mm) and pain quality were assessed. In addition, a comprehensive battery of quantitative sensory tests was conducted, including assessment of mechanical and thermal sensitivity. Neurogenic inflammation was quantified using full-field laser perfusion imaging. Erythema and hyperpigmentation were assessed before, immediately after, and ≈64 hours after AITC exposure. AITC induced significant dose-dependent, moderate-to-severe spontaneous burning pain, mechanical and heat hyperalgesia, and dynamic mechanical allodynia (P < 0.05). No significant differences in induced pain hypersensitivity were observed between the 50% and 90% AITC concentrations. Acute and prolonged inflammation was evoked by all concentrations, and assessments by full-field laser perfusion imaging demonstrated a significant dose-dependent increase with a ceiling effect from 50% to 90%. Topical AITC application produces pain and somatosensory sensitization in a dose-dependent manner with optimal concentrations recommended to be >10% and ≤50%. The model is translatable to humans and could be useful in pharmacological proof-of-concept studies of TRPA1-antagonists, analgesics, and anti-inflammatory compounds or for exploratory clinical purposes, eg, loss- or gain-of-function in peripheral neuropathies.

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“…Potential on‐target adverse effects seem to be less important, because frost injuries are less likely if noxious cold sensation is impaired. Several small‐molecule TRPA1 antagonists showed promising efficacy in animal pain models without unwanted effects . Moreover, clinical proof‐of‐concept is already available by a successful Phase IIa trial in diabetic neuropathic pain proving no safety problems (GRC‐17536, Glenmark Pharmaceuticals, Mumbai, India)…”

Section: Novel Targets With Anti‐inflammatory And/or Analgesic Potentmentioning

confidence: 99%

Challenges to develop novel anti‐inflammatory and analgesic drugs

Botz

Bölcskei

Helyes

2016

WIREs Nanomed Nanobiotechnol

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Chronic inflammatory diseases and persistent pain of different origin represent common medical, social, and economic burden, and their pharmacotherapy is still an unresolved issue. Therefore, there is a great and urgent need to develop anti-inflammatory and analgesic agents with novel mechanisms of action, but it is a very challenging task. The main problem is the relatively large translational gap between the preclinical experimental data and the clinical results due to characteristics of the models, difficulties with the investigational techniques particularly for pain, as well as species differences in the mechanisms. We summarize here the current state-of-the-art medication and related ongoing strategies, and the novel targets with lead molecules under clinical development. The first members of the gold-standard categories, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and opioids, were introduced decades ago, and since then very few drugs with novel mechanisms of action have been successfully taken to the clinics despite considerable development efforts. Several biologics targeting different key molecules have provided breakthrough in some autoimmune/inflammatory diseases, but they are expensive, only parenterally available, their long-term side effects often limit their administration, and they do not effectively reduce pain. Some kinase inhibitors and phosphodiesterase-4 blockers have recently been introduced as new directions. There are in fact some promising novel approaches at different clinical stages of drug development focusing on transient receptor potential vanilloid 1/ankyrin 1 channel antagonism, inhibition of voltage-gated sodium/calcium channels, several enzymes (kinases, semicarbazide-sensitive amine oxidases, and matrix metalloproteinases), cytokines/chemokines, transcription factors, nerve growth factor, and modulation of several G protein-coupled receptors (cannabinoids, purinoceptors, and neuropeptides). WIREs Nanomed Nanobiotechnol 2017, 9:e1427. doi: 10.1002/wnan.1427 For further resources related to this article, please visit the WIREs website.

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Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists

Cited by 45 publications

References 85 publications

Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome

Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome

Dose–response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation

Challenges to develop novel anti‐inflammatory and analgesic drugs

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