Chalcone derivatives as non-canonical ligands of TRPV1

Benso, Bruna; Bustos, Daniel; Zárraga, Miguel; González, Wendy; Caballero, Julio; Brauchi, Sebastián

doi:10.1016/j.biocel.2019.04.010

Cited by 10 publications

(9 citation statements)

References 57 publications

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“…TRPV1 may be activated by various ligands, including derivates of ployunsaturated fatty acids, oxytocin, neurotransmitters, chalcone derivatives, and cannabinoids (42)(43)(44)(45)(46). Cannabinoids are of particular interest, as they have demonstrated some similarities to capsaicin in regard to their anti-inflammatory and anti-tumoral effects in various organs, albeit some of these are mediated by specific receptors (47).…”

Section: Capsaicin and Its Receptor In The Pulmonary Systemmentioning

confidence: 99%

Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review)

et al. 2021

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Chronic obstructive pulmonary disease (COPD) and asthma are chronic respiratory diseases with high prevalence and mortality that significantly alter the quality of life in affected patients. While the cellular and molecular mechanisms engaged in the development and evolution of these two conditions are different, COPD and asthma share a wide array of symptoms and clinical signs that may impede differential diagnosis. However, the distinct signaling pathways regulating cough and airway hyperresponsiveness employ the interaction of different cells, molecules, and receptors. Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a major role in cough and airway inflammation. Consequently, its agonist, capsaicin, is of substantial interest in exploring the cellular effects and regulatory pathways that mediate these respiratory conditions. Increasingly more studies emphasize the use of capsaicin for the inhalation cough challenge, yet the involvement of TRPV1 in cough, bronchoconstriction, and the initiation of inflammation has not been entirely revealed. This review outlines a comparative perspective on the effects of capsaicin and its receptor in the pathophysiology of COPD and asthma, underlying the complex entanglement of molecular signals that bridge the alteration of cellular function with the multitude of clinical effects.

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Section: Capsaicin and Its Receptor In The Pulmonary Systemmentioning

confidence: 99%

Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review)

et al. 2021

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“…Along with their role as molecular sensors in the nociceptive pathway, evidence indicates that TRPV1 channels have a broad physiological function, underscoring their importance in pharmacology and biomedicine. , In contrast to commercially available drugs targeting the inflammatory system, TRPV1 antagonists act as critical negative modulators of nociceptive transduction . Moreover, TRPV1 activation is followed by nerve inactivation, ,, making both potent agonists and antagonists viable tools to promote the desired analgesic effect, provided the necessary pharmacokinetic characteristics are favorable. , In this context, the naturally occurring molecules capsaicin (CAP) and resiniferatoxin (RTx) are well-described vanilloid ligands acting as potent TRPV1 agonists. ,− On the other hand, capsazepine (CPZ), a synthetic derivative of CAP, is an inhibitor of TRPV1 activity. , All three have inhibited nociceptive neuron firing in vitro and in vivo . − Thus, targeting TRPV1 channel activity presents an attractive approach to pain relief that may qualify as the next generation of analgesics. ,, …”

Section: Introductionmentioning

confidence: 99%

“…21,22,29 In this context, small molecules from the secondary metabolism of land plants containing groups similar to those on the CAP's head appear to provide a modular scaffold helpful for the straightforward design of potent and selective ligands for TRPV1. 27,28 Ideal for drug design, CAP's head derivatives are well recognized for the easiness of incorporation into pharmacophores, facilitating repurposing while keeping significant water solubility. 30,31 Here, we aimed to find an economic computational pipeline to combine physicochemical data from in silico analysis with useful pharmacological descriptors.…”

Section: Introductionmentioning

confidence: 99%

Cost-Effective Pipeline for a Rational Design and Selection of Capsaicin Analogues Targeting TRPV1 Channels

et al. 2023

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Transient receptor potential (TRP) channels constitute a large group of membrane receptors associated with sensory pathways in vertebrates. One of the most studied is TRPV1, a polymodal receptor tuned for detecting heat and pungent compounds. Specific inhibition of the nociceptive transduction at the peripheral nerve represents a convenient approach to pain relief. While acting as a chemoreceptor, TRPV1 shows high sensitivity and selectivity for capsaicin. In contrast to the drugs available on the market that target the inflammatory system, TRPV1 antagonists act as negative modulators of nociceptive transduction. Therefore, the development of compounds modulating TRPV1 activity has expanded dramatically over time. Experimental data suggest that most agonist and antagonist drugs interact at or near capsaicin's binding site. In particular, the properties of capsaicin's head play an essential role in modulating potency and affinity. Here, we explored a cost-efficient pipeline to predict the effects of introducing chemical modifications into capsaicin's head region. An extensive set of molecules was selected by first considering the geometrical properties of capsaicin's binding site and then molecular docking. Finally, the novel ligands were ranked by combining molecular and pharmacokinetic predictions.

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“…In capsaicin and natural capsaicin‐like compounds, vanillyl was identified as an essential group to modulate TRPV1. Subsequently, a wide number of TRVP1 ligands have been synthesised that have other groups instead of vanillyl, such as pyrimidine 16 , 2-benzothiazolyl acetamide 17 , catechol 18 , 19 , chalcone 20 , 2–(3-fluoro-4-methylsulfonylaminophenyl)propanamide 21 , etc.…”

Section: Introductionmentioning

confidence: 99%

A new era for the design of TRPV1 antagonists and agonists with the use of structural information and molecular docking of capsaicin-like compounds

Caballero

2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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The design of TRPV1 antagonists and agonists has reached a new era since TRPV1 structures at near-atomic resolution are available. Today, the ligand-binding forms of several classical antagonists and agonists are known; therefore, the specific role of key TRPV1’s residues in binding of ligands can be elucidated. It is possible to place the well-defined pharmacophore of TRPV1 ligands, conformed by head, neck, and tail groups, in the right pocket regions of TRPV1. It will allow a more thorough use of molecular modelling methods to conduct more effective rational drug design protocols. In this work, important points about the interactions between TRPV1 and capsaicin-like compounds are spelled out, based on the known pharmacophore of the ligands and the already available TRPV1 structures. These points must be addressed to generate reliable poses of novel candidates and should be considered during the design of novel TRPV1 antagonists and agonists.

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Chalcone derivatives as non-canonical ligands of TRPV1

Cited by 10 publications

References 57 publications

Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review)

Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review)

Cost-Effective Pipeline for a Rational Design and Selection of Capsaicin Analogues Targeting TRPV1 Channels

A new era for the design of TRPV1 antagonists and agonists with the use of structural information and molecular docking of capsaicin-like compounds

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