Antagonism of GABA_B‐receptor‐mediated responses in the guinea‐pig isolated ileum and vas deferens by phosphono‐analogues of GABA

Abstract

1 The phosphono-analogues of y-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 GABAB-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 6-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 GABAA-receptors, nor influenced the ileal twitch depression with morphine, adenosine or noradrenaline, suggesting their selectivity as antagonists at GABAB-receptors.

Tonic Activation of Presynaptic GABAB Receptors in the Opener Neuromuscular Junction of Crayfish

“…In addition, we have confirmed that the more potent antagonist 2-OH-saclofen is effective against baclofen at the crayfish GABA B receptors, as was originally shown by Fischer and Parnas (1996a). In particular, we have established the concentration-dependent depression of excitatory transmitter release by baclofen at the crayfish opener neuromuscular system, with an EC 50 value of 30 M and a maximum depression of 87% at 150 M. We made two different estimates of potency for phaclofen as an antagonist at the crustacean GABA B receptors, both of which gave a mean value of pA 2 ϭ 4.3, close to the pA 2 value of 4.0 previously obtained for phaclofen in the mammal (Kerr et al 1990). In addition, we found that the phosphonic analogue of GABA, 3-APPA, itself partly reduced transmitter release, yet attenuated the action of baclofen when coapplied.…”

Multiple receptors for calcitonin gene‐related peptide and amylin on guinea‐pig ileum and vas deferens

“…The vas deferens was stimulated transmurally using a Grass S48 stimulator with 1 s trains of pulses of 0.5 ms width, 70 V amplitude at 20 Hz, repeated at 25 s intervals (Ellis & Burnstock, 1989). The ileum was stimulated transmurally using a Scientific and Research Instrument Ltd. (U.K.) stimulator with 0.1 ms pulses, 10 V amplitude at a frequency of 0.1 Hz (Kerr et al, 1990). Cumulative concentration-response curves to agonist alone were constructed, allowing 5 min between each addition of drug.…”

Poster Communications

“…These were transmurally stimulated, with trains of rectangular pulses at 0.04Hz. Each train was of Is duration consisting of 20 pulses of 0.5ms pulse width, 70V stimulation amplitude (adapted from Kerr et al, 1990). Cumulative concentration-response curves were constructed.…”