Ong J, Marino V, Parker D A, Kerr D I
Department of Anaesthesia and Intensive Care, The University of Adelaide, South Australia.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Apr;357(4):408-12. doi: 10.1007/pl00005186.
The effects of five phosphonic derivatives of GABA on the release of [3H]-GABA from rat neocortical slices, preloaded with [3H]-GABA, were investigated. Phaclofen and 4-aminobutylphosphonic acid (4-ABPA) increased the overflow of [3H] evoked by electrical stimulation (2 Hz) in a concentration-dependent manner, with similar potencies (phaclofen EC50=0.3 mmol/l, 4-ABPA EC50=0.4 mmol/l). At 3 mmol/l, phaclofen increased the release of [3H]-GABA by 82.6+/-8.6%, and 4-ABPA increased the release by 81.3+/-9.0%. 2-Amino-ethylphosphonic acid (2-AEPA) increased the overflow of [3H] by 46.8+/-10.9% at the highest concentration tested (3 mmol/l). In contrast, the lower phosphonic homologue 3-aminopropylphosphonic acid (3-APPA), and 2-amino-2-(p-chlorophenyl)-ethylphosphonic acid (2-CPEPA), a baclofen analogue, did not modify the stimulated overflow. These results suggest that phaclofen, 4-ABPA and 2-AEPA are antagonists at GABA(B) autoreceptors, the latter being the weakest antagonist, whilst neither 3-APPA nor 2-CPEPA are active at these receptors. Since phaclofen, 4-ABPA and 2-CPEPA are antagonists and 3-APPA a partial agonist/antagonist on GABA(B) heteroreceptors, the lack of effect of 3-APPA and 2-CPEPA on [3H]-GABA release in this study suggests that GABA(B) autoreceptors may be pharmacologically distinct from the heteroreceptors.
研究了γ-氨基丁酸（GABA）的五种膦酸衍生物对预先加载了[³H]-GABA的大鼠新皮质切片中[³H]-GABA释放的影响。巴氯芬和4-氨基丁基膦酸（4-ABPA）以浓度依赖性方式增加电刺激（2Hz）诱发的[³H]溢出，效力相似（巴氯芬EC50 = 0.3mmol/L，4-ABPA EC50 = 0.4mmol/L）。在3mmol/L时，巴氯芬使[³H]-GABA的释放增加了82.6±8.6%，4-ABPA使释放增加了81.3±9.0%。2-氨基乙基膦酸（2-AEPA）在测试的最高浓度（3mmol/L）下使[³H]溢出增加了46.8±10.9%。相比之下，较低的膦酸同系物3-氨基丙基膦酸（3-APPA）和巴氯芬类似物2-氨基-2-（对氯苯基）-乙基膦酸（2-CPEPA）并未改变刺激引起的溢出。这些结果表明，巴氯芬、4-ABPA和2-AEPA是GABA(B)自身受体的拮抗剂，后者是最弱的拮抗剂，而3-APPA和2-CPEPA在这些受体上均无活性。由于巴氯芬、4-ABPA和2-CPEPA是GABA(B)异源受体的拮抗剂，而3-APPA是部分激动剂/拮抗剂，本研究中3-APPA和2-CPEPA对[³H]-GABA释放缺乏影响表明，GABA(B)自身受体在药理学上可能与异源受体不同。
