CONVERSION OF THE SODIUM-CHANNEL ACTIVATOR ACONITINE INTO A POTENT ALPHA-7-SELECTIVE NICOTINIC LIGAND

Methyllycaconitine (MLA) is a competitive antagonist of nicotinic acetylcholine receptors, with a remarkable preference for neuronal [I-125]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 [I-125]alpha Bgt binding sites 2500-fold and abolished affinity for [H-3]nicotine and muscle [I-125]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 [I-125]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.