The morpholino-acetic acid analogue Sch 50911 is a selective GABA B receptor antagonist in rat neocortical slices

Abstract

The pharmacological properties of (+)-( S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) were evaluated on GABA B receptors in rat neocortical slices. The GABA B receptor agonist, baclofen, produced a concentration-dependent depression of the frequency of spontaneous discharges in slices maintained in Mg 2+-free Krebs medium with an EC 50 of 6 μM, reversibly antagonised by Sch 50911 (5, 10 and 25 μM) with an apparent pA 2 of 6.0±0.1. The (−) enantiomer Sch 50910 (500 μM) and the racemic des-methyl analogue Sch 48588 (500 μM) were inactive. In slices preloaded with [ 3 H ]GABA, Sch 50911 antagonised GABA B autoreceptors, increasing the electrically-stimulated 3 H overflow in a concentration-dependent manner, with an IC 50 of 3 μM. The maximal effect (148±10.5%) was found at 10 μM, but at 50 μM the response was reduced to 67±19%. In contrast, evoked release was unaffected by Sch 50910 (100 μM) whilst Sch 48588 at 100 μM increased the overflow by 51.3±11.6%. In summary, Sch 50911 is a relatively potent antagonist of considerable potential in studies of GABA B receptor function.