Pharmacological Characterization of (3S)-3-(Hydroxymethyl)-4-(5-Methylpyridin-2-yl)-N-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-3,4-Dihydro-2H-Benzo[b][1,4]Oxazine-8-Carboxamide (JTS-653), a Novel Transient Receptor Potential Vanilloid 1 Antagonist

Kitagawa, Yoshihiro; Miyai, Atsuko; Usui, Kenji; Hamada, Yuji; Deai, Katsuya; Wada, Masashi; Koga, Yoshihisa; Sakata, Masahiro; Hayashi, Mikio; Tominaga, Makoto; Matsushita, Mutsuyoshi

doi:10.1124/jpet.112.194027

Cited by 16 publications

(8 citation statements)

References 35 publications

(55 reference statements)

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“…Nilius and Szallasi point at 2 compounds, PHE377 and JTS‐653, as potential exceptions, but do not support their claim with data. The polymodal antagonist JTS‐653 has been reported to potently block proton‐induced activation of both rat and human TRPV1 channels and to cause hyperthermia in rats; therefore, it fully fits the proposed model. As for PHE377, no data regarding this compound have been published in the peer‐reviewed literature.…”

Section: Discussionsupporting

confidence: 56%

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

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AimThermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.MethodsTwo hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.ResultsAdministered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1 −/− mice, even though both compounds evoked pronounced hypothermia in Trpv1 +/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.Conclusion TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.SignificanceTRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

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Section: Discussionsupporting

confidence: 56%

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

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“…JTS‐653 (Fig. ) has been studied for the potential treatment of postherpetic neuralgia (phase II completed) and overactive bladder pain (Phase II discontinued) . XEN‐D0501 (chemical structure not disclosed) entered clinical development for the indications of chronic cough and COPD (phase II completed, http://ClinicalTrials.gov Identifier: NCT02233699, NCT02233686).…”

Section: Clinical Trialsmentioning

confidence: 99%

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

Tabrizi

Baraldi

et al. 2016

Medicinal Research Reviews

118

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Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel.

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“…TRPV1 channels play an important role in inflammatory mechanical allodynia (Gavva et al ., ; Yu et al ., ; Hillery et al ., ; Kitagawa et al ., ). On testing LE135 in a model of mechanical allodynia, using the von Frey method (Caterina et al ., ; Petrus et al ., ), we found that intraplantar injection of LE135 substantially reduced the mechanical threshold of the injected hindpaws.…”

Section: Resultsmentioning

confidence: 97%

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels

Yin

Luo

Qian

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSERetinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho [2,3-b] [1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ, is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. EXPERIMENTAL APPROACHWe performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. KEY RESULTSLE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. CONCLUSIONS AND IMPLICATIONSThis blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels.

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Pharmacological Characterization of (3S)-3-(Hydroxymethyl)-4-(5-Methylpyridin-2-yl)-N-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-3,4-Dihydro-2H-Benzo[b][1,4]Oxazine-8-Carboxamide (JTS-653), a Novel Transient Receptor Potential Vanilloid 1 Antagonist

Abstract: Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S) -

Cited by 16 publications

References 35 publications

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels

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