Martin R J, Sitamze J M, Duittoz A H, Wermuth C G
Department of Preclinical Veterinary Sciences R. (D.) S.V.S., University of Edinburgh, UK.
Eur J Pharmacol. 1995 Mar 24;276(1-2):9-19. doi: 10.1016/0014-2999(94)00778-6.
The structure-activity relationships of 35 novel derivatives of 2-(carboxypropyl)-3-amino-4-methyl-6-phenyl pyridazine (SR 95103) were examined as gamma-aminobutyric acid (GABA) antagonists in the flap preparation of the parasitic nematode, Ascaris suum, using a two-microelectrode current-clamp technique. All but one of the potent antagonists displaced GABA dose-response curves to the right without reduction in the maximum response. The dissociation constants of the more potent competitive antagonists were described using a model which assumed that two molecules of GABA were required to open the ion channel but that only one molecule of antagonist acted on each ion channel. By exploring the structure-activity relationship, the potency of the antagonist was increased from a KB of 64 microM for SR 95103 to a KB of 4.7 microM for NCS 281-93 (2-(3-carboxypropyl)-3-amino-4-phenylpropyl-6-phenyl pyridazine).
利用双微电极电流钳技术，在猪蛔虫这种寄生线虫的皮瓣制备实验中，研究了2-(羧丙基)-3-氨基-4-甲基-6-苯基哒嗪（SR 95103）的35种新型衍生物作为γ-氨基丁酸（GABA）拮抗剂的构效关系。除一种强效拮抗剂外，其余所有拮抗剂均使GABA剂量反应曲线右移，且最大反应未降低。使用一种模型描述了更强效竞争性拮抗剂的解离常数，该模型假定打开离子通道需要两个GABA分子，但每个离子通道上仅一个拮抗剂分子起作用。通过探索构效关系，拮抗剂的效价从SR 95103的KB为64微摩尔增加到NCS 281-93（2-(3-羧丙基)-3-氨基-4-苯基丙基-6-苯基哒嗪）的KB为4.7微摩尔。
