Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel

Petrocellis, Luciano De; Moriello, Aniello Schiano; Byun, Joon Seok; Sohn, Joo Mi; Lee, Jae Yeol; Vázquez-Romero, Ana; Garrido, M del R; Messeguer, Àngel; Zhang, Fang-Xiong; Zamponi, Gerald W.; Deplano, Alessandro; Congiu, Cenzo; Onnis, Valentina; Balboni, Gianfranco; Marzo, Vincenzo Di

doi:10.1016/j.phrs.2015.07.009

Cited by 6 publications

(4 citation statements)

References 61 publications

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“…KYS-05090S did not have any further effects in Cav3.2 null mice, indicating that its mechanism of action is dependent on this T-type channel isoform. This result is somewhat surprising since, in addition to its effect on Cav3.2, KYS-05090S has also been shown to inhibit native TRPV1 channels in vitro [8] and is also able to block recombinant Cav2.2 channels with an affinity of ∼5 μM [26], both of which are known targets for analgesics. In particular, it is well established that TRPV1 is a major Asterisks denote the significance relative to the control group (Cav3.2+/+ vehicle); ***P<0.001 (one-way ANOVA followed by Tukey's test).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, targeting multiple types of ion channels that are involved in the processing of pain signals may be a useful strategy for the development of new pain therapeutics. A recent series of studies has reported on both in vitro and in vivo effects of a series of 3,4-dihydroquinazoline derivatives [8,26]. One of the derivatives, KYS-05090S (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain

M’Dahoma

Gadotti

Zhang

et al. 2015

Pflugers Arch - Eur J Physiol

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T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in half-inactivation potential. KYS-05090S was then tested in models of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS-05090S mediates a potent analgesic effect in inflammatory and neuropathic pain through T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain

M’Dahoma

Gadotti

Zhang

et al. 2015

Pflugers Arch - Eur J Physiol

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“…One such study treated mice with a selective TRPV1 antagonist, A-889425, and identified a corresponding blockade of pain-relaying A-delta nerve fibers, indicating a potential avenue for novel nociceptive modulation [31]. Another group discovered a highly selective an potent antagonist, KYS-05090, to TRPV1 and proposed potential clinical utility [32]. Finally, antibodies directed against TRPV1 channels have been developed [33].…”

Section: Transient Receptor Potential Cation Channel (Trp) Pharmacmentioning

confidence: 99%

Pain transduction: a pharmacologic perspective

McEntire

Kirkpatrick

Dueck

et al. 2016

Expert Review of Clinical Pharmacology

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Pain represents a necessary physiological function yet remains a significant pathological process in humans across the world. The transduction of a nociceptive stimulus refers to the processes that turn a noxious stimulus into a transmissible neurological signal. This involves a number of ion channels that facilitate the conversion of nociceptive stimulus into an electrical signal. Because an understanding of nociceptive physiology complements a discussion of analgesic pharmacology, the relationships between the two are presented together. In this review article, a critical evaluation is provided on the findings relating to both the physiology and pharmacology of relevant acid-sensing ion channels (ASIC), and transient receptor potential (TRP) cation channels, and voltage-gated sodium (Nav) channels.

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“…In particular, DCs express TRPV1. And evidence suggests that TRPV1 modulates maturation of DCs through AMPK activation (Baskaran, Krishnan, Ren, & Thyagarajan, 2016;Ching et al, 2012;De Petrocellis et al, 2015; B. H. Li et al, 2014;Omari, Adams, & Geraghty, 2017).…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory effect of oleoylethanolamide in dendritic cells via TRPV1/AMPK activation

Yao

Zhang

Huang

et al. 2019

Journal Cellular Physiology

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Oleoylethanolamide (OEA) is an endogenous lipid mediator involved in the control of feeding, body weight, and energy metabolism. However, whether OEA modulates maturation of dendritic cells (DCs) has never been addressed. Hence, we evaluated the effect of OEA on DCs maturation in bone marrow‐derived DCs (BMDCs) in four aspects: (a) Cell surface markers were determined using flow cytometric analysis; (b) cell mobile ability was testified with the transwell assay; (c) stimulation of T cells proliferation was performed in a coculture system; and (d) cytokine production was measured using polymerase chain reaction (PCR). The result showed that, in mature BMDCs induced by lipopolysaccharides (LPS), the OEA treatment decreased expressions of cell surface markers, reduced cell migration, diminished the proliferation of cocultured T cells, and regulated cytokine production of BMDCs, indicating the modulatory effect of OEA on DCs maturation. Furthermore, to explore the underlying mechanism of the immunomodulatory effect of OEA, we used antagonists of transient receptor potential vanilloid‐1 (TRPV1) and AMP‐activated protein kinase (AMPK), determined the protein expressions of TRPV1/AMPK and Toll‐like receptor 4 (TLR4)/nuclear factor‐kappa B (NF‐κB) using western blot, and measured the intracellular calcium concentration using calcium imaging. The result illustrated that OEA downregulated TLR4/NF‐κB, the classical pathway leading to DCs maturation induced by LPS, through the activation of TRPV1 and AMPK. Collectively, the present study suggests that OEA suppresses DCs maturation through the activation of TRPV1/AMPK. These findings increase our understanding of this endogenous lipid OEA.

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Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel

Cited by 6 publications

References 61 publications

Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain

Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain

Pain transduction: a pharmacologic perspective

Immunomodulatory effect of oleoylethanolamide in dendritic cells via TRPV1/AMPK activation

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