Conversion of the sodium channel activator aconitine into a potent α7‐selective nicotinic ligand

FEBS Letters

Cooper, Gary¹  Potter, Barry V.L.¹  Scott-Ward, Toby²  Hardick, David J.¹  Wonnacott, Susan²  Blagbrough, Ian S.¹ 

[1] School of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK;School of Biology and Biochemistry, 4 West, University of Bath, Bath BA2 7AY, UK

关键词: Methyllycaconitine;    Aconitine;    α-Bungarotoxin;    [3H]Nicotine;    Nicotinic receptor subtype;    Tetrodotoxin;    Veratridine;   

DOI  :  10.1016/0014-5793(95)00426-A

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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

【 授权许可】

Unknown