<i>N</i>-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2<i>H</i>)-carbox-amide  (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with  Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic  Properties

Valenzano, Kenneth J.; Grant, Elfrida R.; Wu, Gang; Hachicha, Mohamed; Schmid, Lori; Tafesse, Laykea; Sun, Qun; Rotshteyn, Yakov; Francis, Joseph W.; Limberis, James T.; Malik, Shiazah; Whittemore, Edward R.; Hodges, Dianne

doi:10.1124/jpet.102.045674

Cited by 200 publications

(133 citation statements)

References 39 publications

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“…Capsazepine was from Alexis (San Diego, CA). The syntheses of olvanil, DA-5018 (Jung et al, 1999), BCTC (Valenzano et al, 2003), and JYL-1511 were by standard methods. The syntheses of CHK-679, HCR-211, HCR-331, MK-484, PSY-279, YHS-369 will be described elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors

Pearce

Tóth

Ryu

et al. 2008

Naunyn-Schmied Arch Pharmacol

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The transient receptor potential V1 channel (vanilloid receptor, TRPV1) represents a promising therapeutic target for inflammatory pain and other conditions involving C-fiber sensory afferent neurons. Sensitivity of TRPV1 is known to be subject to modulation by numerous signaling pathways, in particular by phosphorylation, and we wished to determine whether TRPV1 structure-activity relations could be differentially affected. We demonstrate here that the structure activity relations of TRPV1, as determined by 45 Ca 2+ uptake, were substantially altered by treatment of the cells with cyclosporin A, an inhibitor of protein phosphatase 2B. Whereas the potency of resiniferatoxin for stimulation of 45 Ca 2+ was not altered by cyclosporin A treatment, the potencies of some other agonists were increased up to 8-fold. Among antagonists examined, potencies were reduced to a lesser extent, ranging from 1-2.5 fold. Finally, the efficacy of partial agonists was increased. In contrast to cyclosporin A, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, had little effect on agonist potencies, and calyculin A, an inhibitor of protein phosphatases 1 and 2A but with somewhat different selectivity from that of okadaic acid, caused changes in structure activity relations distinct from those induced by cyclosporin A. Because phosphatase activity differentially modulates the structure activity relations of TRPV1 agonists and antagonists, our findings predict that it may be possible to design agonist and antagonists selective for TRPV1 in a specific regulatory environment. A further implication is that it may be desirable to tailor screening approaches for drug discovery to reflect the desired regulatory state of the targeted TRPV1.

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Section: Methodsmentioning

confidence: 99%

Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors

Pearce

Tóth

Ryu

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…BCTC is an interesting compound that modulates various thermoTRP channels: it blocks TRPV1 (Valenzano et al, 2003;Behrendt et al, 2004) and cold-and menthol-evoked responses mediated by TRPM8 in native and expressed channels (Behrendt et al, 2004;Madrid et al, 2006). In contrast, it activates recombinant TRPA1 channels (Madrid et al, 2006).…”

Section: Nodose Cs Neurons Respond Specifically To Trpa1 Agonistsmentioning

confidence: 99%

TRPA1 Channels Mediate Cold Temperature Sensing in Mammalian Vagal Sensory Neurons: Pharmacological and Genetic Evidence

Fajardo

Meseguer²,

Belmonte³

et al. 2008

J. Neurosci.

146

118

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“…3A). To test whether calcium influx through active TRPM8 channels located at the PM was enough to induce this recruitment, we used the TRPM8 blocker BCTC (Valenzano et al, 2003). One minute incubation with BCTC (10 M) was enough to occlude the effect of menthol (200 M) on vesicle recruitment (Fig.…”

Section: Menthol-induced Recruitment Of Vesicles Depends On Trpm8 Conmentioning

confidence: 99%

Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor TRPM8

Toro

Eger

Veliz³

et al. 2015

J. Neurosci.

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The spatial and temporal distribution of receptors constitutes an important mechanism for controlling the magnitude of cellular responses. Several members of the transient receptor potential (TRP) ion channel family can regulate their function by modulating their expression at the plasma membrane (PM) through rapid vesicular translocation and fusion. The mechanisms underlying this regulation are not completely understood, and the contribution of vesicular trafficking to physiological function is unknown. TRPM8 receptors are expressed in mammalian peripheral sensory neurons and are essential for the detection of cold temperatures. Previously, we showed that TRPM8-containing vesicles are segregated into three main pools, immobile at the PM, simple diffusive and corralled-hopping. Here, we show that channel expression at the PM is modulated by TRPM8 agonists in F11 and HEK293T cells. Our results support a model in which the activation of TRPM8 channels, located at the PM, induces a short-lived recruitment of a TRPM8-containing vesicular pool to the cell surface causing a transitory increase in the number of functional channels, affecting intrinsic properties of cold receptor responses. We further demonstrate the requirement of intact vesicular trafficking to support sustained cold responses in the skin of mice.

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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

Cited by 200 publications

References 39 publications

Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors

Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors

TRPA1 Channels Mediate Cold Temperature Sensing in Mammalian Vagal Sensory Neurons: Pharmacological and Genetic Evidence

Agonist-Dependent Modulation of Cell Surface Expression of the Cold Receptor TRPM8

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