SB-205384 - A GABA(A) 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 exp ressed in Xenopus oocytes by electrophysiological methods. 2 The slowi ng of the decay rate induced by SB-205384 on native GABA-activated cur rents in rat neurones was also seen on GABA(A) currents in oocytes exp ressing human GABA(A) subunits. This temporal effect was observed for the alpha 3 beta 2 gamma 2 subunit combination with little effect in s ubunit combinations containing either alpha 1 or alpha 2. 3 Potentiati on of the peak amplitude of the GABA-activated currents by SB-205384 o r (+)-SB-205384 was less specific for a particular subunit combination , although the greatest effect at 10 mu M drug was seen on the alpha 3 beta 2 gamma 2 subunit combination. 4 In contrast, zolpidem, a benzod iazepine site modulator, did not significantly slow decay rates of GAB A(A) currents in oocytes expressing the alpha 3 beta 2 gamma 2 subunit combination. Zolpidem, as expected, did selectively potentiate GABA-a ctivated currents on oocytes expressing the gamma 2 subunit compared t o those containing the gamma 1. 5 The results show that the never kine tic modulatory profile of SB-205384 is selective for the alpha 3 beta 2 gamma 2 subunit combination. This suggests that the compound is bind ing to a novel regulatory site on the subunit complex.