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

Abstract

In rat neocortical slices maintained in Mg 2+-free Krebs medium, baclofen depressed the rate of spontaneous discharges in a concentration-dependent manner (EC 50=4.5 μM). This depression was reversibly antagonised by 5-( S, R)-hydroxymethyl-5-methyl-morpholinyl-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 slices preloaded with [ 3 H ]γ-aminobutyric acid (GABA), Sch 54679 (EC 50=3 μM) was 2.3 times more potent than Sch 51324 (EC 50=7 μM) in increasing [ 3 H ]GABA release through antagonism of GABA B autoreceptors. These structurally novel analogues may be pharmacologically useful for elucidating GABA B receptor functions.