Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4-[3-Chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity.

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Activation of TRPV1 channels leads to stimulation of NKCC1 cotransport in the lens

AJP Cell Physiology ◽

10.1152/ajpcell.00252.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. C793-C802 ◽

Cited By ~ 8

Author(s):

Mohammad Shahidullah ◽

Amritlal Mandal ◽

Nicholas A. Delamere

Keyword(s):

Ion Transport ◽

Transient Receptor Potential ◽

Ion Homeostasis ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Signaling Mechanism ◽

Trpv1 Channels ◽

Trpv1 Antagonist ◽

Transient Receptor ◽

Stimulation Of

Lens ion homeostasis is crucial in maintaining water content and, in turn, refractive index and transparency of the multicellular syncytium-like structure. New information is emerging on the regulation of ion transport in the lens by mechanisms that rely on transient receptor potential vanilloid (TRPV) ion channels. We found recently that TRPV1 activation leads to Ca2+/PKC-dependent ERK1/2 signaling. Here, we show that the TRPV1 agonist capsaicin (100 nM) and hyperosmotic solution (350 vs. 300 mosM) each caused an increase of bumetanide-inhibitable Rb uptake by intact porcine lenses and Na-K-2Cl cotransporter 1 (NKCC1) phosphorylation in the lens epithelium. The TRPV1 antagonist A889425 (1 µM) abolished the increases of Rb uptake and NKCC1 phosphorylation in response to hyperosmotic solution. Exposing lenses to hyperosmotic solution in the presence of MEK/ERK inhibitor U0126 (10 µM) or the with-no-lysine kinase (WNK) inhibitor WNK463 (1 µM) also prevented NKCC1 phosphorylation and the Rb uptake responses to hyperosmotic solution. WNK463 did not prevent the increase in ERK1/2 phosphorylation that occurs in response to capsaicin or hyperosmotic solution, suggesting that ERK1/2 activation occurs before WNK activation in the sequence of signaling events. Taken together, the evidence indicates that activation of TRPV1 is a critical early step in a signaling mechanism that responds to a hyperosmotic stimulus, possibly lens shrinkage. By activating ERK1/2 and WNK, TRPV1 activation leads to NKCC1 phosphorylation and stimulation of NKCC1-mediated ion transport.

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Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4)

ACS Medicinal Chemistry Letters ◽

10.1021/acsmedchemlett.9b00274 ◽

2019 ◽

Vol 10 (8) ◽

pp. 1228-1233 ◽

Cited By ~ 9

Author(s):

Carl A. Brooks ◽

Linda S. Barton ◽

David J. Behm ◽

Hilary S. Eidam ◽

Ryan M. Fox ◽

...

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Transient Receptor ◽

Clinical Candidate

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Modulation of the Transient Receptor Potential Vanilloid Channel TRPV4 by 4α-Phorbol Esters: A Structure−Activity Study

Journal of Medicinal Chemistry ◽

10.1021/jm9001007 ◽

2009 ◽

Vol 52 (9) ◽

pp. 2933-2939 ◽

Cited By ~ 47

Author(s):

Thomas Kjær Klausen ◽

Alberto Pagani ◽

Alberto Minassi ◽

Abdellah Ech-Chahad ◽

Jean Prenen ◽

...

Keyword(s):

Transient Receptor Potential ◽

Phorbol Esters ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Structure Activity ◽

Transient Receptor

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Transient receptor potential vanilloid 1 mediates cocaine reinstatement via the D1 dopamine receptor in the nucleus accumbens

Journal of Psychopharmacology ◽

10.1177/0269881119864943 ◽

2019 ◽

Vol 33 (12) ◽

pp. 1491-1500 ◽

Cited By ~ 1

Author(s):

In-Jee You ◽

Sa-Ik Hong ◽

Shi-Xun Ma ◽

Thi-Lien Nguyen ◽

Seung-Hwan Kwon ◽

...

Keyword(s):

Nucleus Accumbens ◽

Transient Receptor Potential ◽

Drugs Of Abuse ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Skf 81297 ◽

Genetic Deletion ◽

Trpv1 Antagonist ◽

Transient Receptor ◽

Cocaine Reinstatement

Purpose: The transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that mediates synaptic modification in the nucleus accumbens (NAc). However, no study has yet examined the mechanism of TRPV1 in the NAc on cocaine reinstatement. We investigated the mechanism of TRPV1 in NAc on cocaine reinstatement using the conditioned place preference (CPP) test in mice. Methods: We examined the effect of capsazepine (5 mg/kg, a TRPV1 antagonist, administered intraperitoneally (i.p.)), capsaicin (0.3 mg/kg, a TRPV1 agonist, administered i.p.), and genetic deletion of TRPV1 on the reinstatement of cocaine-induced CPP (15 mg/kg, administered i.p.). The expression of TRPV1 and Ca2+/calmodulin-mediated kinase II (CaMKII) in the NAc were determined after cocaine reinstatement. Microinjection of SB366791 (0.2 ng, a selective TRPV1 antagonist) in the NAc was assessed on SKF-81297 (1 µg, D1-like dopamine (DA) receptor agonist) primed cocaine reinstatement. Results: Capsazepine suppressed and capsaicin potentiated cocaine CPP in the reinstatement phase. In addition, genetic deletion of TRPV1 inhibited cocaine-priming reinstatement. Cocaine reinstatement was mediated by increased TRPV1 expression in the NAc, which involves CaMKII. Microinjection of SB366791 in the NAc prevented the cocaine reinstatement evoked by microinjection of SKF-81297 in the NAc. Conclusions: These findings suggest that activation of TRPV1 mediates the stimulation of D1-like DA receptors and CaMKII in the NAc, resulting in the facilitation of cocaine reinstatement behaviors. Thus, our findings reveal a previously unknown TRPV1 mechanism in the reinstatement to drugs of abuse.

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