title: Blocking actions of picrotoxinin analogues on insect (Periplaneta americana) GABA receptors.
abstract: Five picrotoxinin analogues were examined on GABA-gated chloride channels of an identifiable cockroach (Periplaneta americana) motor neurone (Df). Substitution of the bridgehead hydroxyl at the C-6 position of the picrotoxinin molecule by a fluorine atom (fluoropicrotoxinin) had little effect, whereas acetylation of the same functional group (picrotoxinin acetate) substantially reduced the effectiveness of the parent compound. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity. Dendrobine, a naturally-occurring picrotoxinin-like compound had very little effect on GABA-induced responses at concentrations up to 1.0 x 10(-5) M. The present results suggest that the size and the ability of the bridgehead hydroxyl to undergo hydrogen bond formation and the lipophilic nature of the terminal isopropenyl group profoundly affect the inhibitory actions of the picrotoxinin molecule on insect neuronal GABA-gated chloride channels.
authors.affiliation: AFRC Laboratory of Molecular Signalling, Department of Zoology, University of Cambridge, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Anthony
authors.forename: C W
authors.initials: CW
authors.lastname: Holyoke
authors.forename: D B
authors.initials: DB
authors.lastname: Sattelle
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D018756:GABA Antagonists; D017952:Ganglia, Invertebrate / Q000166:cytology / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D010526:Periplaneta / Q000502:physiology*; D010852:Picrotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D054830:Sesterterpenes
chemical_list: D000470:Alkaloids; D000697:Central Nervous System Stimulants; D018118:Chloride Channels; D018756:GABA Antagonists; D010852:Picrotoxin; D054830:Sesterterpenes; C002077:dendrobine; C022961:picrotoxinin