title: Detailed analysis of (-)-palmyrolide a and some synthetic derivatives as voltage-gated sodium channel antagonists.
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.
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine , Omaha, Nebraska 68178, United States.
authors.forename: Suneet
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Duggan
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Tello-Aburto
authors.forename: Tara D
authors.initials: TD
authors.lastname: Newar
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
authors.forename: William A
authors.initials: WA
authors.lastname: Maio
mesh_terms: D000818:Animals; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D013237:Stereoisomerism; D014701:Veratridine / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018942:Macrolides; D061567:Voltage-Gated Sodium Channel Blockers; C572829:palmyrolide A; D014701:Veratridine