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Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch.

Publication ,  Journal Article
Chandra, S; Wang, Z; Tao, X; Chen, O; Luo, X; Ji, R-R; Bortsov, AV
Published in: Anesthesiology
September 2020

BACKGROUND: Voltage-gated sodium channel Nav1.7 has been validated as a perspective target for selective inhibitors with analgesic and anti-itch activity. The objective of this study was to discover new candidate compounds with Nav1.7 inhibitor properties. The authors hypothesized that their approach would yield at least one new compound that inhibits sodium currents in vitro and exerts analgesic and anti-itch effects in mice. METHODS: In silico structure-based similarity search of 1.5 million compounds followed by docking to the Nav1.7 voltage sensor of Domain 4 and molecular dynamics simulation was performed. Patch clamp experiments in Nav1.7-expressing human embryonic kidney 293 cells and in mouse and human dorsal root ganglion neurons were conducted to test sodium current inhibition. Formalin-induced inflammatory pain model, paclitaxel-induced neuropathic pain model, histamine-induced itch model, and mouse lymphoma model of chronic itch were used to confirm in vivo activity of the selected compound. RESULTS: After in silico screening, nine compounds were selected for experimental assessment in vitro. Of those, four compounds inhibited sodium currents in Nav1.7-expressing human embryonic kidney 293 cells by 29% or greater (P < 0.05). Compound 9 (3-(1-benzyl-1H-indol-3-yl)-3-(3-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)propanamide, referred to as DA-0218) reduced sodium current by 80% with a 50% inhibition concentration of 0.74 μM (95% CI, 0.35 to 1.56 μM), but had no effects on Nav1.5-expressing human embryonic kidney 293 cells. In mouse and human dorsal root ganglion neurons, DA-0218 reduced sodium currents by 17% (95% CI, 6 to 28%) and 22% (95% CI, 9 to 35%), respectively. The inhibition was greatly potentiated in paclitaxel-treated mouse neurons. Intraperitoneal and intrathecal administration of the compound reduced formalin-induced phase II inflammatory pain behavior in mice by 76% (95% CI, 48 to 100%) and 80% (95% CI, 68 to 92%), respectively. Intrathecal administration of DA-0218 produced acute reduction in paclitaxel-induced mechanical allodynia, and inhibited histamine-induced acute itch and lymphoma-induced chronic itch. CONCLUSIONS: This study's computer-aided drug discovery approach yielded a new Nav1.7 inhibitor that shows analgesic and anti-pruritic activity in mouse models.

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Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

September 2020

Volume

133

Issue

3

Start / End Page

611 / 627

Location

United States

Related Subject Headings

  • Voltage-Gated Sodium Channel Blockers
  • Pruritus
  • Neuralgia
  • NAV1.7 Voltage-Gated Sodium Channel
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
  • Female
  • Drug Design
 

Citation

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ICMJE
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Chandra, S., Wang, Z., Tao, X., Chen, O., Luo, X., Ji, R.-R., & Bortsov, A. V. (2020). Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch. Anesthesiology, 133(3), 611–627. https://doi.org/10.1097/ALN.0000000000003427
Chandra, Sharat, Zilong Wang, Xueshu Tao, Ouyang Chen, Xin Luo, Ru-Rong Ji, and Andrey V. Bortsov. “Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch.Anesthesiology 133, no. 3 (September 2020): 611–27. https://doi.org/10.1097/ALN.0000000000003427.
Chandra S, Wang Z, Tao X, Chen O, Luo X, Ji R-R, et al. Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch. Anesthesiology. 2020 Sep;133(3):611–27.
Chandra, Sharat, et al. “Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch.Anesthesiology, vol. 133, no. 3, Sept. 2020, pp. 611–27. Pubmed, doi:10.1097/ALN.0000000000003427.
Chandra S, Wang Z, Tao X, Chen O, Luo X, Ji R-R, Bortsov AV. Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch. Anesthesiology. 2020 Sep;133(3):611–627.

Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

September 2020

Volume

133

Issue

3

Start / End Page

611 / 627

Location

United States

Related Subject Headings

  • Voltage-Gated Sodium Channel Blockers
  • Pruritus
  • Neuralgia
  • NAV1.7 Voltage-Gated Sodium Channel
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
  • Female
  • Drug Design