Benzodiazepine site inverse agonists can selectively inhibit subtypes of the GABAA receptor.

Using the two-electrode voltage-clamp technique, we have evaluated the effects of several inverse agonists on GABA current amplitude in Xenopus oocytes. Oocytes were injected with cRNA coding for primate alpha 1, alpha 2, or alpha 3 subunits in combination with beta 1 gamma 2, beta 2 gamma 2, or beta 3 gamma 2 subunits. In the presence of CGS 8216, we observed greater inhibition in alpha 1 beta 1 gamma 2, alpha 1 beta 2 gamma 2, alpha 1 beta 3 gamma 2, and alpha 3 beta 1 gamma 2 subunit combinations than in other subunit combinations (p < 0.022). DMCM also showed subunit selective inhibition (p < 0.035) whereas FG 7142 did not (p > 0.075). The above findings indicate that drug structure, alpha subunits, and beta subunits interact to influence the magnitude of inhibition of GABAA R subtypes.