ANTAGONISM OF GABA-B-RECEPTOR-MEDIATED RESPONSES IN THE GUINEA-PIG ISOLATED ILEUM AND VAS-DEFERENS BY PHOSPHONO-ANALOGS OF GABA

1. The phosphono-analogues of γ-aminobutyric acid (GABA), 4-amino-butylphosphonic acid (4-ABPA), 3-amino-2-(4-chlorophenyl)-propylphosphonic acid (phaclofen) and 3-amino-2-cyclohexylpropylphosphonic acid, each antagonized the GABA- and baclofen-induced GABA(B)-receptor-mediated depression of twitch responses to transmural stimulation in the guinea-pig isolated ileum, in a concentration-dependent, reversible and surmountable manner (apparent pA2=4.0±0.1, 4±0.2 and 3.7±0.2 respectively, compared with 3.9±0.1 for δ-aminovaleric acid). No such activity was found in a variety of related analogues. 2. By contrast, 3-amino-propylphosphonic acid (3-APPA) behaved as a partial agonist, itself partly depressing ileal twitch contractions in a manner sensitive to 4-ABPA and phaclofen, as well as antagonizing the depression of the ileal twitch by GABA and baclofen (apparent pA2=4.0±0.2). 3. Both 4-ABPA and phaclofen also antagonized the baclofen-induced depression of the twitch in the guinea-pig isolated vas deferens (apparent pA2=4.0±0.1 for each), whilst 3-APPA behaved as a partial agonist, slightly depressing the vas twitch, and antagonised the baclofen-induced depression of the twitch (apparent pA2=3.9±0.1). 4. None of these phosphono-analogues exhibited any action at ileal GABA(A)-receptors, nor influenced the ileal twitch depression with morphine, adenosine or noradrenaline, suggesting their selectivity as antagonists at GABA(B)-receptors.