Antagonism of GABA(B) receptors by morpholino-2-acetic acid derivatives Sch 54679 and Sch 51324 in rat brain

In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen de pressed the rate of spontaneous discharges in a concentration-dependent man ner (EC50 = 4.5 mu M) This depression was reversibly antagonised by 5-(S, R )-hydroxymethyl-5-methylmorpholinyl-2-(R,S)-acetic acid (Sch 54679) and 2-( R,S)-5-[spirocyclopentyl]-morpholinyl-acetic acid (Sch 51324) (respective p A(2) values of 5.8 +/- 0.15 and 5.4 +/- 0.2). In electrically-stimulated sl ices preloaded with [H-3]gamma-aminobutyric acid (GABA), Sch 54679 (EC50 = 3 mu M) was 2.3 times more potent than Sch 51324 (EC50 =7 mu M) in increasi ng [H-3]GABA release through antagonism of GABA, autoreceptors. These struc turally novel analogues may be pharmacologically useful for elucidating GAB A, receptor functions. (C) 1999 Elsevier Science B.V. All rights reserved.