Antagonism of GABAB-receptor-mediated responses in the guinea-pig isolated ileum and vas deferens by phosphono-analogues of GABA.
1. The phosphono-analogues of gamma-aminobutyric acid (GABA), 4-amino-butylphosphonic acid (4-ABPA), 3-amino-2-(4-chlorophenyl)-propylphosphonic acid (phaclofen) and 3-amino-2-cyclohexylpropyl-phosphonic 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 delta-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.
Kerr
D I
DI
Department of Physiology, University of Adelaide, South Australia.
Ong
J
J
Prager
R H
RH
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D000241:Adenosine; D009638:Norepinephrine; D001640:Bicuculline