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Effects of the putative antagonists phaclofen and δ‐aminovaleric acid on GABA B receptor biochemistry
Author(s) -
Robinson T.N.,
Cross A.J.,
Green A.R.,
Toczek J.M.,
Boar B.R.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb14612.x
Subject(s) - baclofen , chemistry , forskolin , gabab receptor , long term potentiation , muscimol , medicine , agonist , endocrinology , receptor , pharmacology , biology , biochemistry
1 Phaclofen and δ‐aminovaleric acid (δ‐AVA) have been reported to be antagonists at γ‐aminobutyric acid B (GABA B ) receptors. Phaclofen, δ‐AVA and related compounds were examined for potency and specificity at GABA B and GABA A receptors in rat cortical membranes labelled with [ 3 H]‐(−)−baclofen and [ 3 H]‐muscimol, respectively. Additionally phaclofen and δ‐AVA were examined in two functional tests of central GABA B 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 (IC 50 = 11.7 μ m ) was 20 fold more potent than phaclofen (IC 50 = 229 μ m ) on GABA B receptor binding. All compounds possessing a phosphonic acid group, including phaclofen, which were active at GABA B receptors were inactive at GABA A receptors, while δ‐AVA was equally potent at both receptors. Several compounds exhibited Hill coefficients of less than unity in displacing [ 3 H]‐(−)−baclofen binding. 3 (−)−Baclofen inhibited forskolin‐stimulated cyclic AMP accumulation (IC 50 = 7.9 μ m ) but this effect was not stereospecific. Phaclofen (1 m m ) was inactive against this inhibition but produced a potentiation of the forskolin effect. δ‐AVA (1 m m ) failed to antagonize the effect of baclofen; rather it mimicked baclofen. 4 (−)−Baclofen (10 μ m ) potentiated isoprenaline‐stimulated cyclic AMP accumulation, an effect antagonized by phaclofen (1 m m ). δ‐AVA (1 m m ) may be a weak antagonist but also potentiated basal cyclic AMP accumulation. 5 We conclude that neither δ‐AVA nor phaclofen are potent specific GABA B receptor antagonists.