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

Suneet Mehrotra, Brendan M. Duggan, Rodolfo Tello-Aburto, Tara D. Newar, William H. Gerwick, Thomas F. Murray, William A. Maio

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)2553-2560
Number of pages8
JournalJournal of Natural Products
Volume77
Issue number11
DOIs
StatePublished - Oct 24 2014

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All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Pharmacology
  • Pharmaceutical Science
  • Analytical Chemistry
  • Organic Chemistry
  • Molecular Medicine
  • Complementary and alternative medicine

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