Abstract
The modulation of [ 35S]t-butylbicyclophosporothionate ([ 35S]TBPS) binding was used to evaluate the actions of the steroid derivative RU 5135 at the γ-aminobutyric acid A (GABA A) receptor complex. The inhibition of [ 35S]TBPS binding by GABA in the presence of various concentrations of RU 5135 was consistent with the hypothesis that RU 5135 is a competitive antagonist at the GABA A receptor. Despite common structural features (i.e., 3α-hydroxylated, 5ß-reduced A ring) with GABA A receptor-active neurosteroids, RU 5135 did not appear to be competitive at the putative steroid site on the GABA A receptor-active, as demonstrated by Schild analysis of 5α-pregnane-3α-ol-20-one (3α,5α-P) modulation of [ 35S]TBPS binding in the presence of different concentrations of RU 5135. On the other hand, the reduced potency of 3α,5α-P as an inhibitor of [ 35S]TBPS binding in the presence of RU 5135, as well as blockade of 5α-pregnane-3α-20α-diol (5α-pregnanediol) inhibition of [ 35S]TBPS binding by RU 5135 provide further support for the GABA A receptor antagonist properties of RU 5135. Moreover, this amidine steroid was able to partially inhibit [ 35S]TBPS binding independent of GABA with nanomolar potency: yet the mechanism by which this occurs remains to be determined.
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