Suramin is a novel competitive antagonist selective to α1β2γ2 GABA over ρ1 GABA receptors.

GABA and GABA receptors are both GABA-gated chloride channels with distinct pharmacological properties, mainly in their sensitivity to bicuculline and gabazine. In this study, we found that suramin, a purinergic receptor antagonist, is a novel competitive antagonist selective to GABA over GABA receptors. Specifically, suramin antagonized the GABA-induced current and the spontaneous opening current of the wild type α1β2γ2 GABA receptor with high-level expression in Xenopus oocytes. The antagonism was concentration dependent with an IC that varied depending on the concentration of GABA, and with the lowest IC of 0.43 μM when antagonizing the spontaneous current. Thus, its potency is slightly higher than bicuculline on the same GABA receptor. Suramin also antagonized the mouse native brain GABA receptors micro-transplanted into the Xenopus oocytes with its potency depending on the GABA concentration. In addition, in the presence of two fixed concentrations of suramin, the GABA concentration response of the receptor was shifted to the right without reduction of the maximum current. Thus, our results are consistent with that suramin is a competitive antagonist for the α1β2γ2 GABA receptor. Interestingly, the rank order of maximum allosteric inhibition (efficacy) of spontaneous current of the GABA receptor by three competitive antagonists was suramin > bicuculline > gabazine, similar to the rank order of their molecular weight. In contrast, similar to bicuculline, suramin has much lower potency in antagonizing the GABA-induced current of the ρ1 GABA receptor. In conclusion, we have identified a novel GABA receptor competitive antagonist, which is selective to the α1β2γ2 over ρ1 GABA receptors.