The morpholino-acetic acid analogue Sch 50911 is a selective GABA(B) receptor antagonist in rat neocortical slices.
The pharmacological properties of (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) were evaluated on GABA(B) receptors in rat neocortical slices. The GABA(B) receptor agonist, baclofen, produced a concentration-dependent depression of the frequency of spontaneous discharges in slices maintained in Mg2+-free Krebs medium with an EC50 of 6 microM, reversibly antagonised by Sch 50911 (5, 10 and 25 microM) with an apparent pA2 of 6.0 +/- 0.1. The (-) enantiomer Sch 50910 (500 microM) and the racemic des-methyl analogue Sch 48588 (500 microM) were inactive. In slices preloaded with [3H]GABA, Sch 50911 antagonised GABA(B) autoreceptors, increasing the electrically-stimulated 3H overflow in a concentration-dependent manner, with an IC50 of 3 microM. The maximal effect (148 +/- 10.5%) was found at 10 microM, but at 50 microM the response was reduced to 67 +/- 19%. In contrast, evoked release was unaffected by Sch 50910 (100 microM) whilst Sch 48588 at 100 microM increased the overflow by 51.3 +/- 11.6%. In summary, Sch 50911 is a relatively potent antagonist of considerable potential in studies of GABA(B) receptor function.
Ong
J
J
Department of Anaesthesia and Intensive Care, The University of Adelaide, South Australia, Australia. jong@medicine.adelaide.edu.au
Marino
V
V
Parker
D A
DA
Kerr
D I
DI
Blythin
D J
DJ
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D019579:Neocortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; C118170:morpholinyl-2-acetic acid; D001418:Baclofen