Common modes of action of γ-butyrolactones and pentylenetetrazol on the GABAA receptor-ionophore complex

Gábor Maksay, Péter Molnár, Lajos Gruber

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Abstract

The effects of pentylenetetrazol and bicyclic γ-butyrolactones of similar stereostructures were studied on the convulsant and benzodiazepine binding sites and chloride ionophore activity of the γ-aminobutyric acid (GABAA) receptor-complex. Bicyclic γ-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [35S]t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyclic γ-butyrolactones decreased their IC50 values by one order of magnitude. The IC50 values of saturated bicyclic γ-butyrolactones and pentylenetetrazol were increased by GABA versus its antagonist R 5135 (3α-hydroxy-16-amino-5β,17-aza-androstan-11-one). A bicyclic γ-butyrolactone and pentylenetetrazol accelerated the dissociation of [35S]TBPS, displaced [3H]flumazenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cortical neurones in culture in a similar manner. These similar effects on binding and ionophore function support their common modes of action on the GABAA receptor-ionophore complex.

Original languageEnglish
Pages (from-to)61-68
Number of pages8
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Volume288
Issue number1
DOIs
Publication statusPublished - Dec 15 1994

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Keywords

  • Benzodiazepine sites
  • Convulsant (picrotoxin) site
  • GABA receptor-ionophore complex
  • Pentylenetetrazol
  • [S]TBPS binding
  • γ-Butyrolactone bicyclic

ASJC Scopus subject areas

  • Pharmacology

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