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TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders

TRPV1, the founding member of the ‘vanilloid’ TRP subfamily, is formerly known as the vanilloid receptor VR1. Vanilloid, because of its archetypal activators, capsaicin and resiniferatoxin, shares a vanillyl moiety essential for bioactivity. Currently, the vanilloid TRP subfamily has six members, TRPV1 to TRPV6, of which TRPV1, V3 and V4 are actively pursued as pharmacological targets.

TRPV1 (Figure 1) is a multifunctional channel involved in thermosensation (heat) and taste perception (e.g., peppers and vinegar). Importantly, TRPV1 also functions as a molecular integrator for a broad range of seemingly unrelated noxious stimuli. In fact, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Chronic capsaicin administration desensitizes TRPV1 and renders the neurons less sensitive to noxious stimuli (painful). This action requires the presence of extracellular Ca2+ and activation of calmodulin-dependent protein kinase which promote channel phosphorylation. This property of capsaicin has been employed for the treatment of pain associated with disease conditions such as diabetic peripheral neuropathy and arthritis.

Figure 1. Topographic structure of the TRPV1 receptor and postulated domains for direct activation and indirect modulation.

Functions of TRPV1 Channel

• TRPV1 in thermal sensation

TRPV1 can be activated at temperatures >43 °C which are responsible for inducing pain in vivo. TRPV1 exhibits a reduced response to noxious stimuli induced by capsaicin, heat and protons in knockout mice. Treatment with selective agonist 2-aminoethoxydiphenyl borate (2-APB), or exposure to temperatures above 40 °C, led to a transient increase in intracellular Ca2+ concentration, which is blocked by pretreatment with selective TRPV1 antagonists. One of the mechanisms responsible for the aspect of inflammation is the modulation of ion channels, such as TRPV1, which become sensitized by mediators in the inflammatory micro-environment. Studies using TRPV1 knockout mice and knockout of receptors for inflammatory mediators demonstrate essential roles for TRPV1 and inflammatory mediators for producing inflammatory pain. The microenvironment created by tissue damage and inflammation is rich in protons produced by inflammatory cells. By activating TRPV1 in these inflamed areas, protons can also contribute to pain sensations. Moreover, TRPV1 expression is up-regulated flowing inflammation and nerve damage which can further enhance the responses mediated by these receptors.

• TRPV1 in diabetes and obesity

Type 1 diabetes has an autoimmune basis involving T cell-targeted destruction of pancreatic islet β cells. TRPV1 is expressed on nerves innervating the islet β cells where they appear to regulate T cell function. An early research demonstrated that administration of capsaicin to neonatal mice was able to destroy the TRPV1 expressing neurons. Interestingly, that treatment protected these mice from autoimmune diabetes. Since TRPV1 neurons play a vital role in modulating inflammation at the level of the pancreatic β cells, it could be as a useful target for controlling inflammation and reducing diabetic symptoms. It has suggested the clinical utility of TRPV1 antagonists or agonist-induced desensitization of TRPV1 to treat type 1 diabetes. TRPV1 has also been implicated in obesity and insulin resistance, characteristic of type 2 diabetes. It is believed that localized inflammation in the pancreas leads to increase in the activity of TRPV1 associated with aging, which contributes to increasing levels of calcitonin gene-related peptide (CGRP). CGRP is known to promote insulin resistance and obesity by decreasing insulin release from β cells. Treatment of Zucker rats with capsaicin or resiniferatoxin (RTX) can reduce fasting plasma insulin and improve glucose tolerance. Overall, these studies suggest that targeting TRPV1 for inhibition could be a novel method for treating insulin resistance and diabetes.

• TRPV1 in ototoxicity of cisplatin

TRPV1 can be expressed in the organ of Corti and spiral ganglion cells. A study shows that capsaicin affected several parameters of auditory function, such as increasing the threshold of auditory nerve compound action potential (CAP) and reducing the magnitude of cochlear microphonics and electrically evoked otoacoustic emissions. Capsaicin is also shown to produce a transient increase in cochlear blood flow. These responses are inhibited by the TRPV1 antagonist capsazepine, implicating TRPV1 in mediating these actions. Recent study shows that TRPV1 is a target of ROS generated by cisplatin. Generation of ROS via NOX3 is shown to be crucial to the activation and induction of TRPV1. Moreover, TRPV1 serves as an integrator of “noxious” stimuli to activation of the inflammatory cascade in the cochlea. These suggest that inhibition of TRPV1 or its downstream effector in the cochlea could provide protection against hearing loss.

TRPV1 antagonists

TRPV1 antagonists can be broadly classified as competitive or non-competitive antagonists. A competitive antagonist binds to the agonist binding site and locks the TRPV1 channel in closed, non-conductive state. Non-competitive antagonists of TRPV1 channel are pore blockers which interact with additional binding sites thereby preventing channel opening by the agonist or blocking its aqueous pore. Non-competitive antagonists can preferentially recognize the population of pathologically-over-activated TRPV1 channels and block them, thereby reducing the potential unwanted side effects. Therefore, they acting as open-channel blockers are therapeutically more attractive. A desirable TRPV1 antagonist should have are two characteristics. Firstly, the TRPV1 antagonist should block all modes of channel activation. Another important feature that is desirable in TRPV1 antagonists is its brain-penetration. The antagonists that penetrate the brain shows more analgesic efficacy than the ones whose actions are limited to the periphery.

In the last 10 years, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. Pharmaceutical industry showed great success in the identification and development of potent small molecule TRPV1 antagonist candidates. To date, at least fifteen compounds entered Phase 1 clinical trials and five of these agents have progressed into Phase 2 ‘proof-of-concept’ studies. However, perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects such as hyperthermia and impaired noxious heat sensation in preclinical animals and men. A series of strategies have been tested to alleviate the hyperthermia caused by TRPV1 antagonists while still preserving their analgesic properties. TRPV1 antagonist-induced hyperthermia is responsive to anti-pyretic agents such as acetaminophen. Hyperthermia caused by TRPV1 antagonists desensitizes after repeated administration of antagonists. Another approach is to chemically modify the pharmacophore structure of TRPV1 antagonists in order to prevent the undesirable side effect of hypothermia while inhibiting all modes of TRPV1 activation.


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For research use only. Not intended for any clinical use.

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