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

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

Author information

1
Department of Pharmacology, Creighton University School of Medicine , Omaha, Nebraska 68178, United States.

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.

PMID:
25343669
PMCID:
PMC4251536
DOI:
10.1021/np500644k
[Indexed for MEDLINE]
Free PMC Article

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