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 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 μ M 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.British Journal of Pharmacology (1998) 123 , 1253–1259; doi: 10.1038/sj.bjp.0701721