Anxiolytic cyclopyrrolone drugs allosterically modulate the binding of [35S]t-butylbicyclophosphorothionate to the benzodiazepine/γ-aminobutyric acid-A receptor/chloride anionophore complex

R. R. Trifiletti, A. M. Snowman, S. H. Snyder

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


The influence of a number of anxiolytic cyclopyrrolone drugs, which include zopiclone and suriclone, on the binding of [35S]t-butylbicyclophosphorothionate (TBPS), to benzodiazepine/γ-aminobutyric acid-A receptor/chloride anionophore complexes has been characterized in rat brain. Suriclone and its metabolites RP35,489 and RP46,166 are the most potent (IC50 ~ 3nM) inhibitors of [35S]TBPS binding thus far described, about an order of magnitude more potent than TBPS itself. The pattern of inhibition of [35S]TBPS binding by suriclone is distinctive; at ~ 10nM there is approximately 50% inhibition of [35S]TBPS binding and inhibition 'plateaus' at this level until suriclone concentrations exceed 1 μM. RP35,489 and RP46,166 display patterns of inhibition similar to suriclone. In saturation studies of [35S]TBPS binding, suriclone reduces the B(max) of [35S]TBPS-binding sites, with little or no effect on K(D). Muscimol also displays a noncompetitive pattern of inhibition of [35S]TBPS binding, whereas inhibition by picrotoxinin appears competitive. [35S]TBPS dissociation is multiphasic and similar whether initiated by 10 μM TBPS or 10 μM picrotoxinin. By contrast, dissociation of [35S]TBPS is much faster (and nearly monophasic) when initiated by 10 μM TBPS/100 nM suriclone, 10 μM TBPS/1 μM muscimol, or 10 μM TBPS/1 mM pentobarbital. These results suggest that suriclone influences [35S]TBPS binding allosterically, at sites distinct from the TBPS/picrotoxinin recognition site. Inhibition of [35S]TBPS binding by suriclone varies regionally with a 'plateau' at ~20% inhibition in the cerebellum, ~50% in the cerebral cortex, hippocampus and brain stem, and ~65% in the striatum and midbrain; by contrast, inhibition of [35S]TBPS by picrotoxinin, muscimol, and pentobarbital shows little regional variation. The inhibition of [35S]TBPS binding by suriclone is reversed by bicuculline [ED50 ~1 μM] in several brain regions examined. Bicuculline alone has little or no influence on [35S]TBPS binding in the cerebral cortex, hippocampus, and cerebellum, but produces a dose-dependent enhancement of [35S]TBPS binding in the striatum, midbrain, and hypothalamus. Regional differences in the effects of suriclone and bicuculline on [35S]TBPS recognition sites suggest possible heterogeneity in the coupling of cyclopyrrolone and bicuculline recognition sites to [35S]TBPS recognition sites in rat brain.

Original languageEnglish (US)
Pages (from-to)470-476
Number of pages7
JournalMolecular Pharmacology
Issue number3
StatePublished - 1984

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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