GABA(B) receptor antagonism by 7-MBFG, a benzo[b]furan analogue of baclofen, in central and peripheral tissues.
(R,S)-4-Amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid (7-MBFG), a new benzofuran analogue of the GABA(B) receptor agonist baclofen, has been evaluated for pharmacological activity on GABA(B) receptors in the guinea-pig isolated ileum and rat neocortical slices. 7-MBFG (300 and 500 microM) reversibly antagonized the (R,S)-baclofen induced depression of cholinergic twitch contractions in the guinea-pig ileum and shifted the concentration-response curve for baclofen to the right, in a parallel manner, giving an apparent pA2 value of 3.7+/-0.3. Likewise, 7-MBFG (300 and 500 microM) reversibly blocked the baclofen-induced suppression of spontaneous discharges, in rat neocortical slices maintained in Mg2+ -free Krebs medium, and caused a rightward, parallel shift of the baclofen concentration-response curve, giving an apparent pA2 value of 4.1+/-0.1. The compound 7-MBFG belongs to a novel, new class of antagonist at central and peripheral GABA(B) receptors, in which the antagonist properties reside in the pseudo-aromatic character of their 3-benzo[b]furan-2-yl substituents, and might provide useful leads for further development of GABA(B) receptor ligands.
Department of Anaesthesia and Intensive Care, The University of Adelaide, South Australia, Australia. jong@medicine.adelaide.edu.au
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J
Ong
D I
DI
Kerr
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M
Ansar
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C
Vaccher
P
P
Berthelot
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D019579:Neocortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
C119114:7-MBFG; D001572:Benzofurans; D002087:Butyrates; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D001418:Baclofen