Department of Life Science and Biotechnology, Shimane University, Matsue, Shimane, Japan.
Bioorg Med Chem Lett. 2011 Mar 15;21(6):1598-600. doi: 10.1016/j.bmcl.2011.01.118. Epub 2011 Feb 2.
γ-Aminobutyric acid (GABA) receptors are postsynaptic membrane protein complexes that are important not only in the regulation of the nervous system but also as targets of drugs and insecticides. We synthesized a photoreactive straight-chain noncompetitive antagonist (NCA), 2-nitro-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl 4-(4-methoxycarbonyl-1-butynyl)benzoate (NMB), to probe the NCA binding site. Our data show that this probe labels the NCA site and demonstrate that the NCA insecticide fipronil binds at a site distinct from that of other NCAs, such as picrotoxinin and 4'-ethynyl-4-n-propylbicycloorthobenzoate. The unique molecule NMB will be useful in identifying the cross-linking site of straight-chain NCAs in GABA receptors and mapping allosteric binding sites. Such studies should provide invaluable information in designing novel NCAs.
γ-氨基丁酸（GABA）受体是突触后膜蛋白复合物，不仅在神经系统的调节中很重要，而且还是药物和杀虫剂的靶标。我们合成了一种光反应性直链非竞争性拮抗剂（NCA），2-硝基-4-[3-（三氟甲基）-3H-重氮-3-基]苯基 4-（4-甲氧羰基-1-丁炔基）苯甲酸酯（NMB），以探测 NCA 结合位点。我们的数据表明，该探针标记了 NCA 位点，并证明 NCA 杀虫剂氟虫腈结合在不同于其他 NCA（如胡椒碱和 4'-乙炔基-4-正丙基双环邻苯二甲酸酯）的位点上。独特的分子 NMB 将有助于识别 GABA 受体中直链 NCA 的交联位点，并绘制变构结合位点。此类研究应为设计新型 NCA 提供宝贵信息。
