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

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.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Hardick DJ,Cooper G,Scott-Ward T,Blagbrough IS,Potter BV,Wonnacott S

doi

10.1016/0014-5793(95)00426-a

subject

Has Abstract

pub_date

1995-05-22 00:00:00

pages

79-82

issue

1

eissn

0014-5793

issn

1873-3468

pii

0014-5793(95)00426-A

journal_volume

365

pub_type

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