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Nonclassical Ion Channels in Depression
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Pharmacologically acute inhibition of TRPC4 and TRPC5 through HC-070 administration was found to decrease anxiety- and depressive-related behavior89. Leptin, which interacts with TRPC1 (and possibly TRPC3) via orexin1, exerts antidepressant effects, and impaired leptin production in a rat model thus contributes to depression-associated behaviors91. Similarly, mice carrying a constitutive knockout allele of TRPC4 were found to exhibit reduced anxiety levels87. Inhibitors of TRPV1 are primarily categorized as either capsaicin or proton blockers; for example SB-705498, which antagonizes capsaicin signaling, was developed as an intranasal medicine for management of neuropathic and inflammatory pain management. Currently, clinical trials are underway to investigate the compound’s efficacy in treating rhinitis, alleviating dental pain, and relieving acute migraine headaches. Research on TRP channels is presently intensifying as further studies emerge on their potential value as drug targets. As more TRP channel subtypes are examined in animal models and clinical trials of psychiatric and neurological diseases, more advanced engineering approaches, such as structural modifications and computer-assisted rational drug design, will also increase the potency and effectiveness of drugs that block these channels.
An update and systematic review on drug therapies for the treatment of refractory chronic cough
Published in Expert Opinion on Pharmacotherapy, 2018
Nicole M. Ryan, Anne E. Vertigan, Surinder S. Birring
TRP channels are expressed in almost every tissue and cell type and play an important role in the regulation of various cell functions. They are able to sense temperature, noxious stimuli, pain, stretch, and osmolarity, and are involved in various diseases through an increased level of channel expression [27]. TRP ion channels are present in the airways, primary airway sensory neurons, smooth muscle, and epithelial cells [21]. In cough, inflammation in the lungs or esophagus increases the afferent nerve excitation [28] that leads to a referred sensation of irritation in the throat and a reduced cough threshold. The reduced cough threshold in refractory CC is associated with increased expression of TRPV1 receptors on airway nerves [29]. Several highly selective TRPV1 antagonists have advanced into clinical development for the treatment of pain. [30,31] One of these TRPV1 antagonists, SB-705498 has been recently trialed in the treatment of refractory CC [32].
Emerging drugs for the treatment of bladder storage dysfunction
Published in Expert Opinion on Emerging Drugs, 2022
The efforts to develop small molecules targeting TRPV1 have produced multiple potent and selective inhibitors (e.g. SB-705498; AMG-517; AZD1386; PHE3779) [see 54], but none of these compounds came close to market authorization. Several reasons contributed to this but the most important is the finding of that acute pharmacological inhibition of TRPV1 evokes hyperthermia, independent of the chemical structure of the antagonist [54]. Thus, there still seems to be no drug candidate on the horizon that can be developed to a clinically useful treatment for LUT disorders, but since the rationale is good further research seems motivated.