2-Hydroxy-saclofen: an improved antagonist at central and peripheral GABAB receptors

Abstract

2-hydroxy-saclofen (2-OH-S), a sulphonic analogue of baclofen, slightly increased the twitch height and reversibly antagonised the GABA- and baclofen-induced depression of twitch contractions in the guinea pig vas deferens and isolated ileum, causing a parallel dextral shift in the baclofen dose-response curve in a competitive manner (pA2 = 5.0) in the latter tissue. 2-OH-S (10-50 microM) reversibly elevated the spike height and antagonised the baclofen (8-20 microM)-induced suppression of ictal discharges in rat cortical slices superfused in Mg2+-free Krebs solution, the spike height declining to control level within 15 min of washout. The antagonism by 2-OH-S on GABAB receptor-mediated actions is selective, as 2-OH-S did not affect depressive responses to adenosine or morphine, or contractile responses to GABA (GABAA receptor-mediated), acetylcholine and carbachol in the ileum. Compared to phaclofen, 2-OH-S is a more potent competitive antagonist of GABAB receptor-mediated actions in the central and peripheral nervous system.