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 Citations (Scopus)

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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Voltage-Gated Sodium Channel Blockers
Veratridine
Derivatives
Macrolides
Sodium
Voltage-Gated Sodium Channels
Enantiomers
Static Electricity
Libraries
Neurons
Electrostatics
Nuclear magnetic resonance
palmyrolide A
Testing

All Science Journal Classification (ASJC) codes

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

Cite this

Detailed analysis of (-)-palmyrolide A and some synthetic derivatives as voltage-gated sodium channel antagonists. / Mehrotra, Suneet; Duggan, Brendan M.; Tello-Aburto, Rodolfo; Newar, Tara D.; Gerwick, William H.; Murray, Thomas F.; Maio, William A.

In: Journal of Natural Products, Vol. 77, No. 11, 24.10.2014, p. 2553-2560.

Research output: Contribution to journalArticle

Mehrotra, Suneet ; Duggan, Brendan M. ; Tello-Aburto, Rodolfo ; Newar, Tara D. ; Gerwick, William H. ; Murray, Thomas F. ; Maio, William A. / Detailed analysis of (-)-palmyrolide A and some synthetic derivatives as voltage-gated sodium channel antagonists. In: Journal of Natural Products. 2014 ; Vol. 77, No. 11. pp. 2553-2560.
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