Bernard Robin Boar

Effects of the putative antagonists phaclofen and δ-aminovaleric acid on GABAB receptor biochemistry

1 Phaclofen and δ‐aminovaleric acid (δ‐AVA) have been reported to be antagonists at γ‐aminobutyric acidB (GABAB) receptors. Phaclofen, δ‐AVA and related compounds were examined for potency and specificity at GABAB and GABAA receptors in rat cortical membranes labelled with [3H]‐(−)−baclofen and [3H]‐muscimol, respectively. Additionally phaclofen and δ‐AVA were examined in two functional tests of central GABAB activity in rat cortical slices, namely the inhibition of forskolin‐stimulated cyclic AMP accumulation, and the potentiation of isoprenaline‐stimulated cyclic AMP accumulation. 2 δ‐AVA (IC50 = 11.7 μm) was 20 fold more potent than phaclofen (IC50 = 229 μm) on GABAB receptor binding. All compounds possessing a phosphonic acid group, including phaclofen, which were active at GABAB receptors were inactive at GABAA receptors, while δ‐AVA was equally potent at both receptors. Several compounds exhibited Hill coefficients of less than unity in displacing [3H]‐(−)−baclofen binding. 3 (−)−Baclofen inhibited forskolin‐stimulated cyclic AMP accumulation (IC50 = 7.9 μm) but this effect was not stereospecific. Phaclofen (1 mm) was inactive against this inhibition but produced a potentiation of the forskolin effect. δ‐AVA (1 mm) failed to antagonize the effect of baclofen; rather it mimicked baclofen. 4 (−)−Baclofen (10 μm) potentiated isoprenaline‐stimulated cyclic AMP accumulation, an effect antagonized by phaclofen (1 mm). δ‐AVA (1 mm) may be a weak antagonist but also potentiated basal cyclic AMP accumulation. 5 We conclude that neither δ‐AVA nor phaclofen are potent specific GABAB receptor antagonists.