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

D J Hardick, Gary Cooper, T Scott-Ward, I S Blagbrough, Barry V.L. Potter, S Wonnacott

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)79-82
Number of pages4
JournalFEBS Letters
Issue number1
Publication statusPublished - 22 May 1995


  • Aconitine
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Brain
  • Bungarotoxins
  • Dopamine
  • Dose-Response Relationship, Drug
  • Ligands
  • Membranes
  • Rats
  • Receptors, Nicotinic
  • Sodium Channel Blockers
  • Structure-Activity Relationship
  • Tetrodotoxin
  • Veratridine


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