GABAB receptor antagonism by 7-MBFG, a benzo[b]furan analogue of baclofen, in central and peripheral tissues

Abstract

(R,S)-4-Amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid (7-MBFG), a new benzofuran analogue of the GABAB receptor agonist baclofen, has been evaluated for pharmacological activity on GABAB receptors in the guinea-pig isolated ileum and rat neocortical slices. 7-MBFG (300 and 500 µM) 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 µM) 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 GABAB 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 GABAB receptor ligands.Key words: (R,S)-baclofen, 4-amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid, GABAB receptor antagonist, rat neocortex, guinea-pig ileum.