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SB‐205384: a GABA A receptor modulator with novel mechanism of action that shows subunit selectivity
Author(s) -
Meadows H J.,
Kumar C S.,
Pritchett D B.,
Blackburn T P.,
Benham C D.
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701721
Subject(s) - protein subunit , zolpidem , gabaa receptor , xenopus , long term potentiation , electrophysiology , chemistry , biophysics , receptor , biology , pharmacology , biochemistry , neuroscience , gene , insomnia
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