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 IC50 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.

中文翻译：

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两种新型合成ADPR类似物对TRPM2通道的选择性抑制。

瞬态受体电位melastatin-2（TRPM2）通道对于监测体内温度至关重要，与神经退行性变等病理过程有关。但是，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标的研究和验证。为了发现新颖的选择性TRPM2抑制剂，合成了一系列腺苷5'-二磷酸核糖类似物，并评估了它们的活性和选择性。全细胞膜片钳记录用于筛选和评估合成的化合物。两种化合物7i和8a被确定为TRPM2抑制剂，IC50分别为5.7和5.4μm。7i和8a都抑制了TRPM2电流，而没有影响TRPM7，TRPM8，TRPV1和TRPV3。