Identification of the hypertension drug niflumic acid as a glycine receptor inhibitor
Identification of the hypertension drug niflumic acid as a glycine receptor inhibitor
复制标题
DOI：
10.1038/s41598-020-70983-2
复制
发表时间：
2020-08-19
影响因子：
4.6
通讯作者：
Hirata, Hiromi
中科院分区：
文献类型：
--
作者：
Ito, Daishi;Kawazoe, Yoshinori;Hirata, Hiromi
甘氨酸是脑干和脊髓中的主要神经递质之一。甘氨酸结合并激活甘氨酸受体（GlyR），增加突触后部位的Cl-传导。这种甘氨酸能突触传递有助于呼吸节律和运动模式的产生。士的宁通过与甘氨酸结合位点结合来抑制GlyR，而印防己毒素通过与通道孔结合来阻断GlyR。我们以前曾报道，浴应用士的宁斑马鱼胚胎引起双侧肌肉收缩，在触觉刺激。为了探索药物介导的GlyRs抑制，我们通过观察斑马鱼胚胎在药物存在下的触摸诱发反应来筛选类似于1，000种已批准药物和抗肿瘤活性分子的化学文库。我们发现，斑马鱼胚胎暴露于硝苯地平（电压门控钙通道抑制剂）或尼氟灭酸（环氧合酶2抑制剂）引起双侧肌肉收缩，就像士的宁处理的胚胎显示。然后，我们分析士的宁，印防己毒素，硝苯地平，硝氟灭酸的浓度依赖性抑制甘氨酸介导的电流的GlyRs在卵母细胞和计算IC（50）。结果表明，它们对GlyR的抑制作用均呈浓度依赖性，其顺序为士的宁>印防己毒素>硝苯地平>硝氟灭酸
Glycine is one of the major neurotransmitters in the brainstem and the spinal cord. Glycine binds to and activates glycine receptors (GlyRs), increasing Cl- conductance at postsynaptic sites. This glycinergic synaptic transmission contributes to the generation of respiratory rhythm and motor patterns. Strychnine inhibits GlyR by binding to glycine-binding site, while picrotoxin blocks GlyR by binding to the channel pore. We have previously reported that bath application of strychnine to zebrafish embryos causes bilateral muscle contractions in response to tactile stimulation. To explore the drug-mediated inhibition of GlyRs, we screened a chemical library of similar to 1,000 approved drugs and pharmacologically active molecules by observing touch-evoked response of zebrafish embryos in the presence of drugs. We found that exposure of zebrafish embryos to nifedipine (an inhibitor of voltage-gated calcium channel) or niflumic acid (an inhibitor of cyclooxygenase 2) caused bilateral muscle contractions just like strychnine-treated embryos showed. We then assayed strychnine, picrotoxin, nifedipine, and niflumic acid for concentration-dependent inhibition of glycine-mediated currents of GlyRs in oocytes and calculated IC(50)s. The results indicate that all of them concentration-dependently inhibit GlyR in the order of strychnine>picrotoxin>nifedipine>niflumic acid.YYY