Inhibition of veratridine-induced delayed inactivation of the voltage-sensitive sodium channel by synthetic analogs of crambescin B.

Abstract

Crambescin B carboxylic acid, a synthetic analog of crambescin B, was recently found to inhibit the voltage-sensitive sodium channels (VSSC) in a cell-based assay using neuroblastoma Neuro 2A cells. In the present study, whole-cell patch-clamp recordings were conducted with three heterologously expressed VSSC subtypes, Nav1.2, Nav1.6 and Nav1.7, in a human embryonic kidney cell line HEK293T to further characterize the inhibition of VSSC by crambescin B carboxylic acid. Contrary to the previous observation, crambescin B carboxylic acid did not inhibit peak current evoked by depolarization from the holding potential of -100mV to the test potential of -10mV in the absence or presence of veratridine (VTD). In the presence of VTD, however, crambescin B carboxylic acid diminished VTD-induced sustained and tail currents through the three VSSC subtypes in a dose-dependent manner, whereas TTX inhibited both the peak current and the VTD-induced sustained and tail currents through all subtypes of VSSC tested. We thus concluded that crambescin B carboxylic acid does not block VSSC in a similar manner to TTX but modulate the action of VTD, thereby causing an apparent block of VSSC in the cell-based assay.

• Authors: Tadaaki Tsukamoto, Yukie Chiba, Atsuo Nakazaki, Yuki Ishikawa, Yoshiki Nakane, Yuko Cho, Mari Yotsu-Yamashita, Toshio Nishikawa, Minoru Wakamori, Keiichi Konoki
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 5 Pg. 1247-1251 (03 01 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28143690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Pyrimidines
• Spiro Compounds
• Voltage-Gated Sodium Channel Blockers
• Voltage-Gated Sodium Channels
• crambescin B
• Veratridine

Topics

• Animals
• Dose-Response Relationship, Drug
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Molecular Structure
• Pyrimidines (chemistry, pharmacology)
• Spiro Compounds (chemistry, pharmacology)
• Veratridine (chemistry, pharmacology)
• Voltage-Gated Sodium Channel Blockers (chemistry, pharmacology)
• Voltage-Gated Sodium Channels (drug effects)