Antagonism of GABA(B) receptors by morpholino-2-acetic acid derivatives Sch 54679 and Sch 51324 in rat brain.
In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen depressed the rate of spontaneous discharges in a concentration-dependent manner (EC50 = 4.5 microM). This depression was reversibly antagonised by 5-(S,R)-hydroxymethyl-5-methylmorpholinyl-2-(R,S)-acetic acid (Sch 54679) and 2-(R,S)-5-[spirocyclopentyl]-morpholinyl-acetic acid (Sch 51324) (respective pA2 values of 5.8+/-0.15 and 5.4+/-0.2). In electrically-stimulated slices preloaded with [3H]gamma-aminobutyric acid (GABA), Sch 54679 (EC50 = 3 microM) was 2.3 times more potent than Sch 51324 (EC50 = 7 microM) in increasing [3H]GABA release through antagonism of GABA(B) autoreceptors. These structurally novel analogues may be pharmacologically useful for elucidating GABA(B) receptor functions.
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; D004558:Electric Stimulation; D004594:Electrophysiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D019579:Neocortex / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D010091:Oximes; C119099:Sch 51324; C119098:Sch 54679; D014316:Tritium; C078793:NNC 711; D005680:gamma-Aminobutyric Acid; D001418:Baclofen