Newly Published
Pain Medicine  |   June 2020
Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch
Author Notes
  • From the Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina (S.C., Z.W., X.T., O.C., X.L., R.-R.J., A.V.B.); and the Departments of Cell Biology (O.C., R.-R.J.) and Neurobiology (R.-R.J.), Duke University Medical Center, Durham, North Carolina
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • This work was presented as a poster presentation at the International Association for the Study of Pain 17th World Congress on Pain in Boston, Massachusetts, September 12 to 16, 2018; and the Rocky Mountain 2019 Bioinformatics Conference in Aspen/Snowmass, Colorado, December 5 to 7, 2019.
    This work was presented as a poster presentation at the International Association for the Study of Pain 17th World Congress on Pain in Boston, Massachusetts, September 12 to 16, 2018; and the Rocky Mountain 2019 Bioinformatics Conference in Aspen/Snowmass, Colorado, December 5 to 7, 2019.×
  • S.C. and Z.W. contributed equally to this article. R.R.J. and A.V.B. contributed equally to this article.
    S.C. and Z.W. contributed equally to this article. R.R.J. and A.V.B. contributed equally to this article.×
  • Submitted for publication January 17, 2020. Accepted for publication May 19, 2020.
    Submitted for publication January 17, 2020. Accepted for publication May 19, 2020.×
  • Correspondence: Address correspondence to Dr. Bortsov: DUMC 3094, 3 Genome Ct., Durham, North Carolina 27710. andrey.bortsov@duke.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine
Pain Medicine   |   June 2020
Computer-aided Discovery of a New Nav1.7 Inhibitor for Treatment of Pain and Itch
Anesthesiology Newly Published on June 26, 2020. doi:https://doi.org/10.1097/ALN.0000000000003427
Anesthesiology Newly Published on June 26, 2020. doi:https://doi.org/10.1097/ALN.0000000000003427
Abstract

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.

Editor’s Perspective:

What We Already Know about This Topic:

  • The Nav1.7 sodium ion channel is of critical importance to pain perception and itch in humans

  • Selective Nav1.7 blockers have not become clinically available for use in pain management

What This Article Tells Us That Is New:

  • In silico screening identified several potential Nav1.7 blocking compounds

  • The combined use of electrophysiology and behavioral pharmacology demonstrated that one compound, DA-0218, was a potent inhibitor of Nav1.7 channels, pain behaviors, and itch in mice