Partial GABA agonist activity of SR 95531 on the binding of [ 35S]TBPS, [ 3H]DMCM and [ 3H]lormetazepam to rat brain membranes

A recently developed series of pyridazinyl-GABA derivatives has been classified as GABA antagonists in electrophysiological, behavioural and biochemical experiments. These substances seemed superior to the classical GABA antagonist bicuculline because of their water-solubility, high potency and apparent selectivity for GABA A receptors. In the present study the most potent representative of this class, SR 95531 almost completely reversed the stimulatory or inhibitory effect of GABA on [ 3H]Iormetazepam and [ 35S]TBPS binding, respectively. To a lesser extent, it antagonized the inhibition of [ 3H]DMCM binding by GABA. However, the interaction of SR 95531 with the GABA receptor seems to be of a complex nature since the compound enhanced the binding of [ 3H]lormetazepam by 28% at 37° in the presence of 200 mM Cl −. Bicuculline inhibited [ 3H]lormetazepam binding under these conditions, presumably by antagonizing the effect of residual endogenous GABA. Similar to GABA and THIP, SR 95531 potently inhibited the binding of [ 3H]DMCM and [ 35S]TBPS, suggesting SR 95531 to be a partial agonist at the GABA Areceptor.