Conversion of the sodium channel activator aconitine into a potent alpha 7-selective nicotinic ligand

FEBS Lett. 1995 May 22;365(1):79-82. doi: 10.1016/0014-5793(95)00426-a.

Abstract

Methyllycaconitine (MLA) is a competitive antagonist of nicotinic acetylcholine receptors, with a remarkable preference for neuronal [125I]alpha Bgt binding sites. We have begun to investigate the structural basis of its potency and subtype selectivity. MLA is a substituted norditerpenoid alkaloid linked to a 2-(methylsuccinimido)benzoyl moiety. Hydrolysis of the ester bond in MLA to produce lycoctonine diminished affinity for rat brain [125I]alpha Bgt binding sites 2500-fold and abolished affinity for [3H]nicotine and muscle [125I]alpha Bgt binding sites. The voltage-gated Na+ channel activator aconitine, also a norditerpenoid alkaloid, but with significant structural differences from lycoctonine, displayed comparable weak or absent nicotinic activity. Addition of a 2-(methylsuccinimido)benzoyl sidechain to O-demethylated aconitine, to mimic MLA, abolished Na+ channel activation and conferred nanomolar affinity for brain [125I]alpha Bgt binding sites, comparable to that of MLA. We propose that the ester-linked 2-(methylsuccinimido)benzoyl group is necessary for nicotinic potency, but alpha 7 selectivity resides in the norditerpenoid core of the molecule.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitine / analogs & derivatives*
  • Aconitine / chemical synthesis
  • Aconitine / chemistry
  • Aconitine / metabolism
  • Aconitine / pharmacology
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Brain / metabolism*
  • Bungarotoxins / pharmacology
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Ligands
  • Membranes / metabolism
  • Rats
  • Receptors, Nicotinic / classification
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / metabolism*
  • Sodium Channel Blockers*
  • Structure-Activity Relationship
  • Tetrodotoxin / pharmacology
  • Veratridine / pharmacology

Substances

  • 3-deoxy-18-O-desmethyl((methylsuccinimido)benzoyl)aconitine
  • 3-deoxy-18-O-desmethyl(2-aminobenzoyl)aconitine
  • Bungarotoxins
  • Ligands
  • Receptors, Nicotinic
  • Sodium Channel Blockers
  • lycoctonine
  • methyllycaconitine
  • Tetrodotoxin
  • Veratridine
  • Dopamine
  • Aconitine