SB-205384: a GABAA receptor modulator with novel mechanism of action that shows subunit selectivity

1. SB-205384, and its (+) enantiomer (+)-SB-205384 were tested for their modulatory effects on human GABA_A receptor subunit combinations expressed in Xenopus oocytes by electrophysiological methods.
2. The slowing of the decay rate induced by SB-205384 on native GABA-activated currents in rat neurones was also seen on GABA_A currents in oocytes expressing human GABA_A subunits. This temporal effect was observed for the α3β2γ2 subunit combination with little effect in subunit combinations containing either α1 or α2.
3. Potentiation of the peak amplitude of the GABA-activated currents by SB-205384 or (+)-SB-205384 was less specific for a particular subunit combination, although the greatest effect at 10 μM drug was seen on the α3β2γ2 subunit combination.
4. In contrast, zolpidem, a benzodiazepine site modulator, did not significantly slow decay rates of GABA_A currents in oocytes expressing the α3β2γ2 subunit combination. Zolpidem, as expected, did selectively potentiate GABA-activated currents on oocytes expressing the γ2 subunit compared to those containing the γ1.
5. The results show that the novel kinetic modulatory profile of SB-205384 is selective for the α3β2γ2 subunit combination. This suggests that the compound is binding to a novel regulatory site on the subunit complex.