Detailed analysis of (-)-palmyrolide a and some synthetic derivatives as voltage-gated sodium channel antagonists

J Nat Prod. 2014 Nov 26;77(11):2553-60. doi: 10.1021/np500644k. Epub 2014 Oct 24.

Abstract

A small library of synthetic (-)-palmyrolide A diastereomers, analogues, and acyclic precursors have been examined with respect to their interaction with voltage-gated sodium channels (VGSCs). Toward this goal, the ability of (-)-palmyrolide A and analogues to antagonize veratridine-stimulated Na(+) influx in primary cultures of mouse cerebrocortical neurons was assessed. We found that synthetic (-)-palmyrolide A and its enantiomer functioned as VGSC antagonists to block veratridine-induced sodium influx. A detailed NMR and computational analysis of four diastereomers revealed that none had the same combination of shape and electrostatic potential as exhibited by natural (-)-palmyrolide A. These data indicate that the relative configuration about the tert-butyl and methyl substituents appears to be a prerequisite for biological function. Additional testing revealed that the enamide double bond was not necessary for blocking veratridine-induced sodium influx, whereas the acyclic analogues and other macrolide diastereomers tested were inactive as inhibitors of VGSCs, suggesting that the intact macrolide was required.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Macrolides / chemistry*
  • Macrolides / pharmacology*
  • Mice
  • Molecular Structure
  • Neurons / drug effects
  • Stereoisomerism
  • Veratridine / pharmacology
  • Voltage-Gated Sodium Channel Blockers / chemistry
  • Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

  • Macrolides
  • Voltage-Gated Sodium Channel Blockers
  • palmyrolide A
  • Veratridine