COMMON-MODES OF ACTION OF GAMMA-BUTYROLACTONES AND PENTYLENETETRAZOL ON THE GABA(A) RECEPTOR-IONOPHORE COMPLEX

The effects of pentylenetetrazol and bicyclic gamma-butyrolactones of similar stereostructures were studied on the convulsant and benzodiaze pine binding sites and chloride ionophore activity of the gamma-aminob utyric acid (GABA(A)) receptor-complex. Bicyclic gamma-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [S-35] t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyc lic gamma-butyrolactones decreased their IC50 values by one order of m agnitude. The IC50 values of saturated bicyclic gamma-butyrolactones a nd pentyienetetrazol were increased by GABA versus its antagonist R 51 35 (3 alpha-hydroxy-16-imino-5 beta,17-aza-androstan-11-one). A bicycl ic gamma-butyrolactone and pentylenetetrazol accelerated the dissociat ion of [S-35]TBPS, displaced [H-3]flumazenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cort ical neurones in culture in a similar manner. These similar effects on binding and ionophore function support their common modes of action o n the GABA(A) receptor-ionophore complex.