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.
Original language | English |
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Pages (from-to) | 79-82 |
Number of pages | 4 |
Journal | FEBS Letters |
Volume | 365 |
Issue number | 1 |
DOIs | |
Publication status | Published - 22 May 1995 |
Keywords
- 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