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

The pharmacological properties of(+)-(S)-5,5-dimethylmorpholinyl-2-acetic a cid (Sch 50911) were evaluated on GABA, receptors in rat neocortical slices . The GABA, receptor agonist, baclofen, produced a concentration-dependent depression of the frequency of spontaneous discharges in slices maintained in Mg2+-free Krebs medium with an EC50 of 6 mu M, reversibly antagonised by Sch 50911 (5, 10 and 25 mu M) with an apparent pA(2) of 6.0 +/- 0.1. The(- )enantiomer Sch 50910 (500 mu M) and the racemic des-methyl analogue Sch 48 588 (500 mu M) were inactive. In slices preloaded with [H-3]GABA, Sch 50911 antagonised GABA, autoreceptors, increasing the electrically-stimulated H- 3 overflow in a concentration-dependent manner, with an IC50 of 3 mu M. The maximal effect (148 +/- 10.5%) was found at 10 mu M, but at 50 mu M the re sponse was reduced to 67 +/- 19%. In contrast, evoked release was unaffecte d by Sch 50910 (100 mu M) whilst Sch 48588 at 100 mu M increased the overfl ow by 51.3 +/- 11.6%. In summary, Sch 50911 is a relatively potent antagoni st of considerable potential in studies of GABA(B) receptor function. (C) 1 998 Elsevier Science B.V. All rights reserved.