Desarmenien M, Desaulles E, Feltz P, Hamann M
Br J Pharmacol. 1987 Feb;90(2):287-98. doi: 10.1111/j.1476-5381.1987.tb08958.x.
A new arylamino-pyridazine gamma-aminobutyric acid (GABA) derivative, SR 42641, has been tested for its ability to antagonize the actions of GABA on mammalian sensory neurones. SR 42641 and bicuculline reversibly decreased GABAA-induced depolarizations and currents recorded intracellularly from dorsal root ganglion neurons (DRG). Dose-response curves were shifted to the right in a parallel fashion. KB values (determined under voltage clamp conditions) were respectively 0.12 +/- 0.05 and 0.38 +/- 0.08 microM. Similar values were obtained with current clamp recording conditions. The study of the GABA-induced Cl- current under voltage-clamp conditions did not show any voltage-dependency of the antagonist effect of SR 42641. In nodose ganglion neurones, SR 42641 (0.4-4.5 microM) did not alter the (-)-baclofen-induced shortening of the calcium component of action potentials. At concentrations higher than 10 microM, SR 42641 itself prolonged calcium-dependent action potentials. Patch-clamp recordings from DRG cultured neurones indicated that SR 42641 did not affect the calcium current responsible for sustained calcium entry into cells. We conclude that SR 42641 is a potent competitive GABA antagonist, specific for the GABAA receptor. It does not act at the level of the chloride ionophore.
一种新型芳基氨基哒嗪γ-氨基丁酸(GABA)衍生物SR 42641,已对其拮抗GABA对哺乳动物感觉神经元作用的能力进行了测试。SR 42641和荷包牡丹碱可逆地降低了从背根神经节神经元(DRG)细胞内记录的GABAA诱导的去极化和电流。剂量-反应曲线以平行方式右移。KB值(在电压钳条件下测定)分别为0.12±0.05和0.38±0.08微摩尔。在电流钳记录条件下获得了相似的值。在电压钳条件下对GABA诱导的Cl-电流的研究未显示SR 42641拮抗作用的任何电压依赖性。在结状神经节神经元中,SR 42641(0.4 - 4.5微摩尔)未改变(-)-巴氯芬诱导的动作电位钙成分缩短。在高于10微摩尔的浓度下,SR 42641本身延长了钙依赖性动作电位。来自DRG培养神经元的膜片钳记录表明,SR 42641不影响负责持续钙内流进入细胞的钙电流。我们得出结论,SR 42641是一种有效的竞争性GABA拮抗剂,对GABAA受体具有特异性。它不作用于氯离子载体水平。