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Conversion of the sodium channel activator aconitine into a potent α7‐selective nicotinic ligand
Author(s) -
Hardick David J.,
Cooper Gary,
Scott-Ward Toby,
Blagbrough Ian S.,
Potter Barry V.L.,
Wonnacott Susan
Publication year - 1995
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(95)00426-a
Subject(s) - methyllycaconitine , chemistry , nicotinic agonist , stereochemistry , aconitine , activator (genetics) , alkaloid , acetylcholine receptor , binding site , nicotinic acetylcholine receptor , biochemistry , receptor , chromatography
Methyllycaconitine (MLA) is a competitive antagonist of nicotinic acetylcholine receptors, with a remarkable preference for neuronal [ 125 I]αBgt 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 [ 125 I]αBgt binding sites 2500‐fold and abolished affinity for [ 3 H]nicotine and muscle [ 125 I]αBgt 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 [ 125 I]αBgt binding sites, comparable to that of MLA. We propose that the ester‐linked 2‐(methylsuccinimido)benzoyl group is necessary for nicotinic potency, but α7 selectivity resides in the norditerpenoid core of the molecule.