A steroid derivative, R 5135, antagonizes the GABA/benzodiazepine receptor interaction

Abstract

A novel steroid derivative, R 5135 (3α-hydroxy-16-imino-5β-17-aza-androstan-11-one) showed high affinity for both the GABA and glycine receptors in vitro. It also displaced [ 3H]diazepam from the benzodiazepine receptor in a rat cortex membrane preparation, but in this case a plateau occurred in the displacement curve at a concentration of R 5135 between 10 −7 and 10 −6 M, where binding was decreased by about 50 %. The “high affinity” component of R 5135 inhibition no longer appeared when the endogenous GABA concentration was reduced by extensive washing of the membrane preparation and it reappeared when GABA was re-introduced. Thus R 5135 behaves as a powerful antagonist of the GABA stimulation of [ 3H]diazepam binding, being 500 times more active than the GABA-antagonist bicuculline. The dual interaction between R 5135 and GABA and glycine receptors suggests that these may share some common structural feature or that they have overlapping specificity.