Pharmacology and Antitussive Efficacy of 4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic Acid (5-Trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a Transient Receptor Potential Vanilloid 1 Antagonist in Guinea Pigs

Bhattacharya, Anindya; Scott, Brian; Nasser, Nadia; Ao, Hong; Maher, Michael P.; Dubin, Adrienne E.; Swanson, Devin M.; Shankley, Nigel P.; Wickenden, Alan D.; Chaplan, Sandra R.

doi:10.1124/jpet.107.127258

Cited by 71 publications

(40 citation statements)

References 40 publications

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“…Sensory nerves expressing TRPV1 innervate the airways, and inhalation of capsaicin elicits cough (Laude et al 1993). TRPV1 antagonists have shown efficacy in suppressing cough and airways hyper-responsiveness in guinea pigs induced by capsaicin and citric acid (Bhattacharya et al 2007;Lalloo et al 1995) and, more relevantly, by ovalbumin (Delescluse et al 2012). Cough suppression has been an end point in at least one clinical trial for a TRPV1 antagonist (Eid 2011).…”

Section: Trpv1 Antagonists and Agonists In Vivomentioning

confidence: 98%

Trpv1

Bevan¹,

Quallo²,

Andersson³

2014

Handbook of Experimental Pharmacology

142

125

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TRPV1 is a well-characterised channel expressed by a subset of peripheral sensory neurons involved in pain sensation and also at a number of other neuronal and non-neuronal sites in the mammalian body. Functionally, TRPV1 acts as a sensor for noxious heat (greater than ~42 °C). It can also be activated by some endogenous lipid-derived molecules, acidic solutions (pH < 6.5) and some pungent chemicals and food ingredients such as capsaicin, as well as by toxins such as resiniferatoxin and vanillotoxins. Structurally, TRPV1 subunits have six transmembrane (TM) domains with intracellular N- (containing 6 ankyrin-like repeats) and C-termini and a pore region between TM5 and TM6 containing sites that are important for channel activation and ion selectivity. The N- and C- termini have residues and regions that are sites for phosphorylation/dephosphorylation and PI(4,5)P2 binding, which regulate TRPV1 sensitivity and membrane insertion. The channel has several interacting proteins, some of which (e.g. AKAP79/150) are important for TRPV1 phosphorylation. Four TRPV1 subunits form a non-selective, outwardly rectifying ion channel permeable to monovalent and divalent cations with a single-channel conductance of 50-100 pS. TRPV1 channel kinetics reveal multiple open and closed states, and several models for channel activation by voltage, ligand binding and temperature have been proposed. Studies with TRPV1 agonists and antagonists and Trpv1 (-/-) mice have suggested a role for TRPV1 in pain, thermoregulation and osmoregulation, as well as in cough and overactive bladder. TRPV1 antagonists have advanced to clinical trials where findings of drug-induced hyperthermia and loss of heat sensitivity have raised questions about the viability of this therapeutic approach.

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Section: Trpv1 Antagonists and Agonists In Vivomentioning

confidence: 98%

Trpv1

Bevan¹,

Quallo²,

Andersson³

2014

Handbook of Experimental Pharmacology

142

125

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“…While TRPV1 is activated at relatively low pH, inflammatory mediators and injury signals can augment the sensitivity of TRPV1 to acidity, and acidity can in turn hypersensitize TRPV1 (73). While it is unlikely that the pH in the lung would drop low enough to activate TRPV1 during inhalation of a TIH, repeated inhalation or underlying inflammation may facilitate TRPV1 to become hypersensitive and therefore triggered by an exposure to a gaseous acid (73)(74)(75)(76)(77)(78)(79)(80). For instance, TRPV1 is sensitized by the potent proinflammatory signal, bradykinin (81).…”

Section: Acid-sensing Ion Channels: Trpv1mentioning

confidence: 99%

Sensory Detection and Responses to Toxic Gases: Mechanisms, Health Effects, and Countermeasures

Bessac

Jordt²

2010

Proceedings of the American Thoracic Society

117

112

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The inhalation of reactive gases and vapors can lead to severe damage of the airways and lung, compromising the function of the respiratory system. Exposures to oxidizing, electrophilic, acidic, or basic gases frequently occur in occupational and ambient environments. Corrosive gases and vapors such as chlorine, phosgene, and chloropicrin were used as warfare agents and in terrorist acts. Chemical airway exposures are detected by the olfactory, gustatory, and nociceptive sensory systems that initiate protective physiological and behavioral responses. This review focuses on the role of airway nociceptive sensory neurons in chemical sensing and discusses the recent discovery of neuronal receptors for reactive chemicals. Using physiological, imaging, and genetic approaches, Transient Receptor Potential (TRP) ion channels in sensory neurons were shown to respond to a wide range of noxious chemical stimuli, initiating pain, respiratory depression, cough, glandular secretions, and other protective responses. TRPA1, a TRP ion channel expressed in chemosensory C-fibers, is activated by almost all oxidizing and electrophilic chemicals, including chlorine, acrolein, tear gas agents, and methyl isocyanate, the highly noxious chemical released in the Bhopal disaster. Chemicals likely activate TRPA1 through covalent protein modification. Animal studies using TRPA1 antagonists or TRPA1-deficient mice confirmed the role of TRPA1 in chemically induced respiratory reflexes, pain, and inflammation in vivo. New research shows that sensory neurons are not merely passive sensors of chemical exposures. Sensory channels such as TRPA1 are essential for maintenance of airway inflammation in asthma and may contribute to the progression of airway injury following high-level chemical exposures.

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“…A recent paper has shown that citric acid evoked coughing in anesthetized guinea pigs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves most likely through sequential activation of acid-sensing ion channels and chloride channels without the contribution of TRPV1 (Canning et al 2006). However, previous studies using first-generation antagonists (Lalloo et al 1995;Trevisani et al 2004) and more recent evidence with second-generation and chemically unrelated TRPV1 antagonists (Bhattacharya et al 2007;Leung et al 2007) showed that all these drugs selectively inhibited citric acid induced cough in guinea pigs, thus providing robust circumstantial evidence that TRPV1 contributes to acidic-media-induced cough.…”

Section: Cough and Trpv1mentioning

confidence: 92%

Cough Sensors. II. Transient Receptor Potential Membrane Receptors on Cough Sensors

Materazzi

Nassini

Gatti

et al. 2009

Pharmacology and Therapeutics of Cough

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The transient receptor potential (TRP) family of channels is represented by at least six members in primary sensory neurons. These include the TRP vanilloid subtypes 1 (TRPV1), 2, 3, and 4, the cold and menthol receptor TRPM8, and TRPA1. Much interest has been directed to the study of the TRPV1, because capsaicin has been instrumental in discovering the unique role of a subset of primary sensory neurons in causing nociceptive responses, in activating reflex pathways including cough, and in producing neurogenic inflammation. TRPV1 is now regarded as an integrator of diverse sensory modalities because it undergoes marked plasticity and sensitization through a variety of mechanisms, including activation of G-protein-coupled or tyrosine kinase receptors. Evidence in experimental animals and in patients with airway diseases indicates a marked hypersensitivity to cough induced by TRPV1 agonists. Recent studies with newly developed high-affinity and selective TRPV1 antagonists have revealed that TRPV1 inhibition reduces cough induced by citric acid or antigen challenge.

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Pharmacology and Antitussive Efficacy of 4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic Acid (5-Trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a Transient Receptor Potential Vanilloid 1 Antagonist in Guinea Pigs

Cited by 71 publications

References 40 publications

Trpv1

Trpv1

Sensory Detection and Responses to Toxic Gases: Mechanisms, Health Effects, and Countermeasures

Cough Sensors. II. Transient Receptor Potential Membrane Receptors on Cough Sensors

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