Saclofen

2-Hydroxy-saclofen causes a phaclofen-reversible reduction in population spike amplitude in the rat hippocampal slice.[Pubmed:7768279]

Eur J Pharmacol. 1995 Feb 14;274(1-3):41-6.

2-Hydroxy-Saclofen is known to be active at GABAB receptors in the mammalian central nervous system, and we have investigated its effects on synaptic transmission in the rat hippocampal slice preparation. Orthodromic stimuli were applied to the stratum radiatum, and population spike responses from the CA1 pyramidal cell layer were recorded extracellularly. A second, identical stimulus was applied at a variable interpulse interval (IPI) after the initial conditioning stimulus. GABAergic synaptic inhibition was observed as a decrease in the spike amplitude of the second response compared to the first. Both the GABAB receptor antagonist phaclofen (1 mM) and 2-hydroxy-Saclofen (200 microM) prevented a slow phase of inhibition for IPIs of 200-400 ms. However, these agents differed markedly in their effects on overall synaptic transmission. Phaclofen had no effect on the amplitude of the initial conditioning spike amplitude, whereas 2-hydroxy-Saclofen reduced it significantly, in a manner similar to baclofen (1 microM). The direct actions of 2-hydroxy-Saclofen were unexpected for a pure antagonist of GABAB receptors, but could be prevented by the co-administration of phaclofen (1 mM), but not bicuculline (1 microM). Reduction in conditioning spike amplitude due to antagonism of GABAB autoreceptors on inhibitory interneurones and subsequent enhancement of GABAA tonic inhibition would have been blocked by bicuculline. The blockade of the 2-hydroxy-Saclofen effect by phaclofen implies a GABAB receptor partial agonist action. The possible sites of this action are discussed.

Endogenous GABA release from rat striatal slices: effects of the GABAB receptor antagonist 2-hydroxy-saclofen.[Pubmed:8390105]

Synapse. 1993 May;14(1):16-23.

The reproducibility of endogenous GABA release evoked by multiple periods of electrical field stimulation was examined in rat striatal slices. In these experiments, NO-328 was used to block GABA uptake, and evoked GABA release (overflow) was completely Ca2+ dependent. A seemingly invariant observation in these experiments was that spontaneous GABA release (outflow) progressively decreased as a function of superfusion time and that GABA overflow decreased 25-30% in response to the second of two periods of stimulation (S2/S1 ratios = 0.70 to 0.75). The attenuation of GABA release was not explained by the amount of GABA lost to the superfusion buffer (fractional release), direct depletion of releasable pools of GABA, or slice viability. Furthermore, the decreases in GABA release were not dependent on stimulation frequency (5-15 Hz) or the absolute amount of GABA evoked by electrical stimulation. However, the GABAB receptor antagonist 2-hydroxy-Saclofen (2-OH-Saclofen; 316 microM) not only enhanced GABA overflow, when superfused throughout both periods of stimulation, but also resulted in S2/S1 ratios of unity. When 2-OH-Saclofen was superfused throughout the second stimulation period only, GABA overflow was almost two-fold greater than that evoked by the initial period of stimulation (2-OH-Saclofen-free). In addition, these S2 responses were approximately 30% greater than S1 responses that were observed when 2-OH-Saclofen was present throughout the entire superfusion period. These results indicate that activation of GABAB receptors was involved in the progressive attenuation of GABA release and further emphasize that GABAB receptors play an important role in modulating endogenous GABA release from striatal slices.

The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen.[Pubmed:11082110]

Br J Pharmacol. 2000 Nov;131(6):1050-4.

1. The aim of this study was to characterize the pharmacological profile of the GABA(B1)/GABA(B2) heterodimeric receptor expressed in Chinese hamster ovary (CHO) cells. We have compared receptor binding affinity and functional activity for a series of agonists and antagonists. 2. The chimeric G-protein, G(qi5), was used to couple receptor activation to increases in intracellular calcium for functional studies on the Fluorimetric Imaging Plate Reader (FLIPR), using a stable GABA(B1)/GABA(B2)/G(qi5) CHO cell line. [(3)H]-CGP-54626 was used in radioligand binding studies in membranes prepared from the same cell line. 3. The pharmacological profile of the recombinant GABA(B1/B2) receptor was consistent with that of native GABA(B) receptors in that it was activated by GABA and baclofen and inhibited by CGP-54626A and SCH 50911. 4. Unlike native receptors, the GABA(B1)/GABA(B2)/G(qi5) response was not inhibited by high microMolar concentration of phaclofen, Saclofen or CGP 35348. 5. This raises the possibility that the GABA(B1)/GABA(B2)/G(qi5) recombinant receptor may represent the previously described GABA(B) receptor subtype which is relatively resistant to inhibition by phaclofen.

GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum.[Pubmed:8858312]

Eur J Pharmacol. 1996 Jul 25;308(3):R1-2.

The GABAB receptor antagonist Saclofen (3-amino-2-(4-chlorophenyl)propylsulphonic acid) has been resolved by chiral high-performance liquid chromatography. The enantiomer (R)-Saclofen, but not (S)-Saclofen, reversibly antagonised the (R,S)-baclofen-induced depression of cholinergic twitch contractions in the guinea-pig ileum with an apparent pA2 of 5.3. Also, 2-hydroxy-Saclofen was resolved by the same method, its (S)-enantiomer yielding an apparent pA2 of 5.0. This method provides a convenient resolution of these antagonists.

GABAB receptors and their significance in mammalian pharmacology.[Pubmed:2559518]

Trends Pharmacol Sci. 1989 Oct;10(10):401-7.

Much progress has been made in GABAB receptor pharmacology since the discovery of this receptor in 1980. Selective agonists and antagonists have been developed and a functional role for the receptor as a mediator of slow inhibitory postsynaptic potentials in many brain regions has emerged. In this article, Norman Bowery discusses the evidence for heterogeneity of GABAB receptors, their possible physiological and pathological roles and the therapeutic potential of GABAB receptor agonists and antagonists.