title: 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.
authors.affiliation: School of Pharmacy and Pharmacology, University of Bath, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Hardick
authors.forename: G
authors.initials: G
authors.lastname: Cooper
authors.forename: T
authors.initials: T
authors.lastname: Scott-Ward
authors.forename: I S
authors.initials: IS
authors.lastname: Blagbrough
authors.forename: B V
authors.initials: BV
authors.lastname: Potter
authors.forename: S
authors.initials: S
authors.lastname: Wonnacott
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002038:Bungarotoxins / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008566:Membranes / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D026941:Sodium Channel Blockers; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
chemical_list: C093994:3-deoxy-18-O-desmethyl((methylsuccinimido)benzoyl)aconitine; C093993:3-deoxy-18-O-desmethyl(2-aminobenzoyl)aconitine; D002038:Bungarotoxins; D008024:Ligands; D011978:Receptors, Nicotinic; D026941:Sodium Channel Blockers; C093992:lycoctonine; C054634:methyllycaconitine; D013779:Tetrodotoxin; D014701:Veratridine; D004298:Dopamine; D000157:Aconitine