COMPETITION FOR DIAZEPAM RECEPTOR-BINDING BY DIPHENYLHYDANTOIN AND ITS ENHANCEMENT BY GAMMA-AMINOBUTYRIC ACID

The anticonvulsant diphenylhydantoin competitively inhibited the binding of [3H]diazepam to synaptic membranes of rat cerebral cortex. The Ki was calculated as 0.9 μM. In the presence of γ-aminobutyric acid the Ki was reduced to 0.3 μM. A similar change in Ki was also observed in the presence of muscimol, a potent agonist of γ-aminobutyric acid. γ-Aminobutyric acid also reduced the dissociation constant (Kd) of diazepam binding from 16.7 nM to 3.9 nM. Thus it appears that diphenylhydantoin and diazepam are binding at the same site and the presence of γ-aminobutyric acid increases the affinity of the receptor for each of the drugs. These observations indicate that the anticonvulsant effects of diphenylhydantoin and diazepam may be related to an interaction with a common binding site and to the modification of this binding site by γ-aminobutyric acid. © 1979.