State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Peking University School of Pharmaceutical Sciences, Beijing, China.
Chem Biol Drug Des. 2018 Feb;91(2):552-566. doi: 10.1111/cbdd.13119. Epub 2017 Nov 15.
Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5'-diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole-cell patch-clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC of 5.7 and 5.4 μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure-activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.
瞬时受体电位 melastatin-2（TRPM2）通道对于监测内部体温至关重要，它与神经退行性变等病理过程有关。然而，缺乏选择性和有效的 TRPM2 抑制剂阻碍了对该通道作为药物靶点的研究和验证。为了发现新型和选择性的 TRPM2 抑制剂，合成了一系列腺苷 5'-二磷酸核糖类似物，并对其活性和选择性进行了评价。全细胞膜片钳记录用于筛选和评价合成化合物。两种化合物 7i 和 8a 被鉴定为 TRPM2 抑制剂，IC 分别为 5.7 和 5.4 μm。7i 和 8a 均抑制 TRPM2 电流，而不影响 TRPM7、TRPM8、TRPV1 和 TRPV3。这两种 TRPM2 抑制剂可作为新的药理学工具，进一步研究和验证 TRPM2 通道作为药物靶点，总结的构效关系（SAR）也可能为进一步改善现有抑制剂作为潜在先导化合物提供思路。
