Actions of 4-amino-3-(5-methoxybenzo(b)furan-2-yl) butanoic acid and 4-amino-3-benzo(b)furan-2-yl butanoic acid in the rat spinal cord

Abstract

This study examined whether two putative GABA B receptor antagonists, 4-amino-3-(5-methoxybenzo (b)furan-2-yl) butanoic acid (MBFG) and 4-amino-3-benzo(b)furan-2-yl butanoic acid (BFG), antagonized the antinociception produced by intrathecal (i.t.) administration of the GABA B receptor agonist baclofen in the rat. In rats pretreated with 30 μg i.t. MBFG, the dose-effect relationship of D,L-baclofen was shifted approximately 2-fold and 4-fold tothe right in the tail flick and hot plate tests, respectively. No further shift was obtained in the presence of 60 μg. i.t. MBFG. I.t. injection of MBFG by itself did not alter either tail flick or hot plate latency. These data suggest that MBFG is a GABA B receptor antagonist in the spinal cord in vivo, although of marginal utility. Contrary to expectations, i.t. administration of 30–60 μg BFG alone increased tail flick and hot plate latencies; this increase was partially attenuated by coadministration of the GABA B receptor antagonist phaclofen. Pretreatment with 10 μg i.t. BFG, which was itself without effect on nociceptive threshold, antagonized the antinociceptive effects of 0.3 μg i.t. L-baclofen, but interacted with higher and lower doses of baclofen in a complex manner. These results suggest that BFG acts as weak, partial agonist at GABA B receptors and that it may have additional, non-specific effects in the spinal cord of the rat. The pharmacological properties of BFG, therefore, resemble those of the GABA B receptor partial agonist/antagonist β-phenyl-GABA, to which it bears a strong structural resemblance. Thus, although MBFG and BFG bind to the GABA B receptor with greater affinity than several previously synthesized GABA B receptor antagonists, neither represents a significant advance over the prototypic, competitive GABA B receptor antagonists, phaclofen or 2-hydroxy-saclofen.