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

1. Phaclofen and delta-aminovaleric acid (delta-AVA) have been reported to be antagonists at gamma-aminobutyric acidB (GABAB) receptors. Phaclofen, delta-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 delta-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. delta-AVA (IC50 = 11.7 microM) was 20 fold more potent than phaclofen (IC50 = 229 microM) 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 delta-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 microM) but this effect was not stereospecific. Phaclofen (1 mM) was inactive against this inhibition but produced a potentiation of the forskolin effect. delta-AVA (1 mM) failed to antagonize the effect of baclofen; rather it mimicked baclofen. 4. (-)-Baclofen (10 microM) potentiated isoprenaline-stimulated cyclic AMP accumulation, an effect antagonized by phaclofen (1 mM). delta-AVA (1 mM) may be a weak antagonist but also potentiated basal cyclic AMP accumulation. 5. We conclude that neither delta-AVA nor phaclofen are potent specific GABAB receptor antagonists.