瞬时受体电位(transient receptor potential, TRP)通道是一类位于细胞膜上重要的非电压门控型的阳离子通道，对细胞功能以及信号转导具有重要作用。TRPM2通道是TRP家族中的一个亚型。多数情况下，TRPM2通道的过度激活会导致细胞内Ca²⁺浓度升高，从而介导炎症因子的产生、细胞凋亡等，进而在缺血性脑卒中、癌症、心血管疾病、糖尿病、阿尔茨海默症、帕金森氏病以及慢性炎症等多种疾病过程中扮演重要角色。但是目前已知的TRPM2抑制剂数量和结构骨架类型都相对较少，而且绝大多数对TRPM2通道的抑制作用是非特异性的，作为工具分子无法精确反映TRPM2通道的实际作用。因此，开发新型TRPM2特异性抑制剂具有十分重要的意义。

基于本人硕士研究生期间的工作，在综合分析初步研究结果和相关文献的基础上，本论文开展了两部分关于新型TRPM2抑制剂设计、合成与活性研究的工作。第一部分的研究工作是N-(对戊基桂皮酰基)邻氨基苯甲酸(ACA)类似物的设计合成及其抗缺血性损伤的功能研究。对TRPM2非特异性抑制剂ACA进行结构修饰，累积设计并合成了59个ACA衍生物。采用细胞钙成像初筛结合膜片钳技术确证的方法对合成的ACA衍生物完成了TRPM2通道抑制活性的评价，发现其中一些化合物对TRPM2通道表现出高于ACA的抑制活性，尤其是化合物A22、A23、A30、C7、C12和C16，其IC₅₀值在微摩尔水平。更重要的是，化合物A23对TRPM8、TRPV1通道以及磷脂酶A2(PLA2)仅有微弱的抑制作用或没有抑制作用，表现出对TRPM2通道的选择性。构效关系研究表明：N-苯基肉桂酰胺结构骨架中取代基的位置和电负性对TRPM2抑制活性和选择性起着关键作用。在联苯基团的3’-位置上含有吸电子基团时，化合物的TRPM2抑制活性和选择性均得以提升；而在4-或5-位引入甲基或溴时，化合物的TRPM2抑制活性提高，但是选择性降低。此外，化合物A23在细胞糖氧剥夺再复灌(OGD/R)模型和小鼠短暂性大脑中动脉栓塞(tMCAO)模型中均表现出良好的神经保护作用，与临床上广泛使用的脑保护剂依达拉奉效果相当甚至更好。而且，药物代谢动力学研究显示化合物A23具有较好的类药性质。

第二部分的研究工作是基于2-氨乙氧基二苯酯硼酸(2-APB)三维结构的新型TRPM2抑制剂筛选、结构优化与活性研究。从TRPM2抑制剂2-APB的能量最低构象出发，利用相似性筛选实现骨架跃迁，得到了新型结构骨架的TRPM2抑制剂。之后对以环庚烷并[b]吡啶为母核的先导化合物进行了优化设计。除了系统的对先导化合物每个部分的结构修饰外，我们还通过基于药效团的分子叠合，参考了化合物JNJ-28583113

的结构进行合理设计，累积合成了43个环庚烷并[b]吡啶类化合物。采用细胞钙成像初筛结合膜片钳技术确证的方法对合成的环庚烷并[b]吡啶类化合物完成了TRPM2通道抑制活性的评价，发现其中一些化合物对TRPM2通道表现出高于2-APB的抑制活性，尤其是化合物D5、D8、F7和F12，其IC₅₀值在微摩尔水平。构效关系研究表明：将环庚烷并[b]吡啶母核结构中3-位氰基替换为甲氧羰基、在4-位引入乙氧羰基或者在侧链吡啶环或苯环的对位或间位引入卤素、氰基或三氟甲基可以显著提高抑制效果；而且，中间连接链部分的硫原子替换为氧原子可以使TRPM2抑制活性略有提升。此外，环庚烷并[b]吡啶类化合物E1对TRPM8和TRPV1通道均没有抑制作用，初步显示了对TRPM2通道的选择性。而且点突变研究发现化合物E1可通过与细胞外孔道区域直接结合抑制TRPM2通道，其中氨基酸K952、K958、R961、H995以及D1002均对化合物E1在TRPM2通道上的结合有贡献。

通过本论文的研究，发现了两类高活性与高选择性的TRPM2抑制剂，不仅可以作为进一步研究TRPM2通道相关生理和病理功能的药理学工具，而且可能为TRPM2介导的多种疾病提供潜在的临床治疗药物，具有重要的科学意义。

Transient receptor potential (TRP) channels belong to a novel family of non-voltage-gated cationic ion channels with strong impacts on cellular functions and signalling pathways. Transient receptor potential melastatin 2 (TRPM2), a Ca²⁺-permeable non-selective cation channel that also allows the permeation of Na⁺ and K⁺. Due to its roles in Ca²⁺ mobilization, the TRPM2 channel can participate in many calcium-dependent physiological processes. Extensive researches have further indicated that excessive activation of TRPM2 is associated with ischemia/reperfusion (I/R) injury, inflammatory, cancer and neurodegenerative diseases. However, few TRPM2 inhibitors have been reported, especially TRP-subtype selective inhibitors, which hampers the investigation and validation of TRPM2 as a drug target. Therefore, development of selective TRPM2 inhibitors has attracted increasing attention for both academic functional studies and clinical applications.

According to research during my master’s degree and the reported TRPM2 inhibitors, herein, we conducted two parts of work on the design, synthesis and biological activities of TRPM2 inhibitors. The first one is “the discovery of novel ACA derivatives as specific TRPM2 inhibitors that reduce ischemic injury both in vitro and in vivo.” We designed and synthesized 59 ACA derivatives, and the inhibitory activities of these synthesized compounds against the TRPM2 channel were evaluated by calcium imaging and electrophysiology approaches. Some of them exhibited stronger inhibitory activity against the TRPM2 currents than ACA, particularly compounds A22, A23, A30, C7, C12 and C16, with IC₅₀ values ranging from 398 to 987 nM. More importantly, A23 showed TRPM2 selectivity over TRPM8 and TRPV1 channels, as well as PLA2. SAR studies revealed that compounds containing electron-withdrawing groups at the 3’-position of biphenyl improved the potency and specificity of the TRPM2 channel, while compounds with methyl or bromine introduced at the 4- or 5-position contributed to improving inhibitory activity, but was harmful to the specificity of the TRPM2 channel. These summarized SARs provide valuable insights for the further development of specific TRPM2 inhibitors. Compound A23 exhibited excellent neuroprotective activities both in in vitro OGD/R model and in vivo tMCAO model, which were equal to or even better than the widely used neuroprotectant EDA. Furthermore, the PK studies showed that A23 exhibited high plasma exposure, which was consistent with the pharmacodynamic results.

The second one is “virtual screening, structure optimization and biological activity of novel TRPM2 inhibitors based on 2-APB 3D structure.” We used the optimized conformation of 2-APB as the query structure to discover cyclohepta[b]pyridine derivatives as potent TRPM2 inhibitors. In addition to the systematic structural modification of each part of the lead compound, we also used the pharmacophore-based molecular alignment and the current best active compound JNJ-28583113 to make a rational design. We designed and synthesized 43 cyclohepta[b]pyridine derivatives, and the inhibitory activities of these synthesized compounds against the TRPM2 channel were evaluated by calcium imaging and electrophysiology approaches. Some of them exhibited stronger inhibitory activity against the TRPM2 currents than 2-APB, particularly compounds D5, D8, F7 and F12, with IC₅₀ values ranging from 219 to 471 nM. SAR studies revealed that replacing the cyano at 3-position of cyclohepta[b]pyridine with methoxycarbonyl, introducing ethoxycarbonyl at 4-position of cyclohepta[b]pyridine or introducing halogen, cyano or trifluoromethyl at the m- or p-position of the pyridine or benzene resulted in improved inhibitory activity. And the replacement of sulfur atom with oxygen atom in the linker could slightly increase the inhibitory activity. More importantly, compound E1 showed TRPM2 selectivity over TRPM8 and TRPV1 channels. In addition, point mutation study indicated that E1 inhibited the TRPM2 through interacting with the extracellular pore region, K952, K958, R961, H995 and D1002 were critically involved in the inhibition by compound E1.

Taken together, we discovered two types of TRPM2 inhibitors with both improved potency and specificity, which will not only provide molecular tools for the pharmacological researches to better understand the channel functions, but also lead to the potential clinical therapeutic agents for related diseases.

第一章 文献综述 1
1.1 TRP通道超家族简介 1
1.2 TRPM2通道的结构与门控机制 4
1.3 TRPM2通道的功能及其疾病相关性 12
1.4 抑制剂对TRPM2通道的功能调控 23
1.5 本章小结 30
第二章 ACA类似物的设计合成及其抗缺血性损伤的功能研究 31
2.1 第一轮结构修饰所得化合物的活性评价与构效关系研究 32
2.2 第二轮结构修饰的设计思路与化合物的合成 39
2.3 第二轮结构修饰所得化合物的活性评价与构效关系总结 41
2.4 优选化合物的选择性 45
2.5 优选化合物抗缺血性损伤功能研究 50
2.6 本章小结 55
第三章 基于2-APB三维结构的新型TRPM2抑制剂筛选、结构优化与活性研究 57
3.1 前期工作 58
3.2 化合物的设计与合成 59
3.3 化合物的活性评价与结果讨论 69
3.4 本章小结 82
第四章 总结与展望 84
4.1 总结 84
4.2 展望 85
第五章 实验部分 88
5.1 仪器设备与试剂耗材 88
5.2 化学合成实验部分 90
5.3 生物活性评价部分 109
5.4 计算模拟部分 115
参考文献 119
附录A 终产物一览表 131
附录B 终产物结构表征图谱 138
附录C 部分终产物HPLC图谱 214
附录D 代表性化合物原始电流示意图 223
致谢 225
简历 227
北京大学学位论文原创性声明和使用授权说明 229
学位论文答辩委员会名单 230

[1] Vangeel, L.; Voets, T., Transient Receptor Potential Channels and Calcium Signaling. Cold Spring Harb Perspect Biol. 2019, 11, 145-176.

[2] Tsagareli, M. G.; Nozadze, I., An overview on transient receptor potential channels superfamily. Behavioural Pharmacology. 2020, 31, 413-434.

[3] Sumoza-Toledo, A.; Penner, R., TRPM2: a multifunctional ion channel for calcium signalling. J Physiol. 2011, 589, 1515-1525.

[4] Krylatov, A. V.; Maslov, L. N.; Voronkov, N. S.; Boshchenko, A. A.; Popov, S. V.; Gomez, L.; Wang, H.; Jaggi, A. S.; Downey, J. M., Reactive Oxygen Species as Intracellular Signaling Molecules in the Cardiovascular System. Curr Cardiol Rev. 2018, 14, 290-300.

[5] Sita, G.; Hrelia, P.; Graziosi, A.; Ravegnini, G.; Morroni, F., TRPM2 in the Brain: Role in Health and Disease. Cells. 2018, 7, 55-74.

[6] Tan, C. H.; Mcnaughton, P. A., TRPM2 and warmth sensation. Pflugers Arch. 2018, 470, 787-798.

[7] Miller, B. A., TRPM2 in Cancer. Cell Calcium. 2019, 80, 8-17.

[8] Thapak, P.; Vaidya, B.; Joshi, H. C.; Singh, J. N.; Sharma, S. S., Therapeutic potential of pharmacological agents targeting TRP channels in CNS disorders. Pharmacol Res. 2020, 159, 105-126.

[9] Montell, C.; Rubin, G. M., Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron. 1989, 2, 1313-1323.

[10] Wes, P. D.; Chevesich, J.; Jeromin, A.; Rosenberg, C.; Stetten, G.; Montell, C., TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci. 1995, 92, 9652-9656.

[11] Zhu, X.; Jiang, M.; Peyton, M.; Boulay, G.; Hurst, R.; Stefani, E.; Birnbaumer, L., trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell. 1996, 85, 661-671.

[12] Gaudet, R., Structural Insights into the Function of TRP Channels. In TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades, Liedtke, W. B.; Heller, S., Eds. CRC Press/Taylor & Francis Copyright ? 2007, Taylor & Francis Group, LLC.: Boca Raton (FL), 2007.

[13] Wang, R.; Tu, S.; Zhang, J.; Shao, A., Roles of TRP Channels in Neurological Diseases. Oxid Med Cell Longev. 2020, 19, 728-736.

[14] Nilius, B.; Szallasi, A., Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev. 2014, 66, 676-814.

[15] Samanta, A.; Hughes, T. E. T.; Moiseenkova-Bell, V. Y., Transient Receptor Potential (TRP) Channels. Subcell Biochem. 2018, 87, 141-165.

[16] Aroke, E. N.; Powell-Roach, K. L.; Jaime-Lara, R. B.; Tesfaye, M.; Roy, A.; Jackson, P.; Joseph, P. V., Taste the Pain: The Role of TRP Channels in Pain and Taste Perception. Int J Mol Sci. 2020, 21, 966-1013.

[17] Genova, T.; Gaglioti, D.; Munaron, L., Regulation of Vessel Permeability by TRP Channels. Front Physiol. 2020, 11, 421.

[18] Sakaguchi, R.; Mori, Y., Transient receptor potential (TRP) channels: Biosensors for redox environmental stimuli and cellular status. Free Radic Biol Med. 2020, 146, 36-44.

[19] Spix, B.; Chao, Y. K.; Abrahamian, C.; Chen, C. C.; Grimm, C., TRPML Cation Channels in Inflammation and Immunity. Front Immunol. 2020, 11, 225-236.

[20] Kaneko, Y.; Szallasi, A., Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol. 2014, 171, 2474-2507.

[21] Moran, M. M., TRP Channels as Potential Drug Targets. Annu Rev Pharmacol Toxicol. 2018, 58, 309-330.

[22] Stok?osa, P.; Borgstr?m, A.; Kappel, S.; Peinelt, C., TRP Channels in Digestive Tract Cancers. Int J Mol Sci. 2020, 21, 1425-1437.

[23] Fonfria, E.; Murdock, P. R.; Cusdin, F. S.; Benham, C. D.; Kelsell, R. E.; Mcnulty, S., Tissue distribution profiles of the human TRPM cation channel family. J Recept Signal Transduct Res. 2006, 26, 159-178.

[24] Jimenez, I.; Prado, Y.; Marchant, F.; Otero, C.; Eltit, F.; Cabello-Verrugio, C.; Cerda, O.; Simon, F., TRPM Channels in Human Diseases. Cells. 2020, 9, 236-247.

[25] Mederos Y Schnitzler, M.; W?ring, J.; Gudermann, T.; Chubanov, V., Evolutionary determinants of divergent calcium selectivity of TRPM channels. Faseb J. 2008, 22, 1540-1551.

[26] Bouron, A.; Kiselyov, K.; Oberwinkler, J., Permeation, regulation and control of expression of TRP channels by trace metal ions. Pflugers Arch. 2015, 467, 1143-1164.

[27] Jiang, L. H.; Yang, W.; Zou, J.; Beech, D. J., TRPM2 channel properties, functions and therapeutic potentials. Expert Opin Ther Targets. 2010, 14, 973-988.

[28] Takahashi, N.; Kozai, D.; Kobayashi, R.; Ebert, M.; Mori, Y., Roles of TRPM2 in oxidative stress. Cell Calcium. 2011, 50, 279-287.

[29] Shen, B. W.; Perraud, A. L.; Scharenberg, A.; Stoddard, B. L., The crystal structure and mutational analysis of human NUDT9. J Mol Biol. 2003, 332, 385-398.

[30] Perraud, A. L.; Fleig, A.; Dunn, C. A.; Bagley, L. A.; Launay, P.; Schmitz, C.; Stokes, A. J.; Zhu, Q.; Bessman, M. J.; Penner, R.; Kinet, J. P.; Scharenberg, A. M., ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature. 2001, 411, 595-599.

[31] Iordanov, I.; Mihályi, C.; Tóth, B.; Csanády, L., The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity. Elife. 2016, 5, e12019.

[32] Perraud, A. L.; Takanishi, C. L.; Shen, B.; Kang, S.; Smith, M. K.; Schmitz, C.; Knowles, H. M.; Ferraris, D.; Li, W.; Zhang, J.; Stoddard, B. L.; Scharenberg, A. M., Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J Biol Chem. 2005, 280, 6138-6148.

[33] Perraud, A. L.; Shen, B.; Dunn, C. A.; Rippe, K.; Smith, M. K.; Bessman, M. J.; Stoddard, B. L.; Scharenberg, A. M., NUDT9, a member of the Nudix hydrolase family, is an evolutionarily conserved mitochondrial ADP-ribose pyrophosphatase. J Biol Chem. 2003, 278, 1794-1801.

[34] Belrose, J. C.; Jackson, M. F., TRPM2: a candidate therapeutic target for treating neurological diseases. Acta Pharmacol Sin. 2018, 39, 722-732.

[35] Wehage, E.; Eisfeld, J.; Heiner, I.; Jüngling, E.; Zitt, C.; Lückhoff, A., Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem. 2002, 277, 23150-23156.

[36] Kühn, F. J.; Lückhoff, A., Sites of the NUDT9-H domain critical for ADP-ribose activation of the cation channel TRPM2. J Biol Chem. 2004, 279, 46431-46437.

[37] Kashio, M.; Sokabe, T.; Shintaku, K.; Uematsu, T.; Fukuta, N.; Kobayashi, N.; Mori, Y.; Tominaga, M., Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. Proc Natl Acad Sci. 2012, 109, 6745-6750.

[38] Luo, Y.; Yu, X.; Ma, C.; Luo, J.; Yang, W., Identification of a Novel EF-Loop in the N-terminus of TRPM2 Channel Involved in Calcium Sensitivity. Front Pharmacol. 2018, 9, 581-594.

[39] Huang, Y.; Roth, B.; Lü, W.; Du, J., Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel. Elife. 2019, 8, e21435.

[40] Mei, Z. Z.; Jiang, L. H., Requirement for the N-terminal coiled-coil domain for expression and function, but not subunit interaction of, the ADPR-activated TRPM2 channel. J Membr Biol. 2009, 230, 93-99.

[41] Winking, M.; Hoffmann, D. C.; Kühn, C.; Hilgers, R. D.; Lückhoff, A.; Kühn, F. J., Importance of a conserved sequence motif in transmembrane segment S3 for the gating of human TRPM8 and TRPM2. PLoS One. 2012, 7, e49877.

[42] Yang, W.; Manna, P. T.; Zou, J.; Luo, J.; Beech, D. J.; Sivaprasadarao, A.; Jiang, L. H., Zinc inactivates melastatin transient receptor potential 2 channels via the outer pore. J Biol Chem. 2011, 286, 23789-23798.

[43] Yu, W.; Jiang, L. H.; Zheng, Y.; Hu, X.; Luo, J.; Yang, W., Inactivation of TRPM2 channels by extracellular divalent copper. PLoS One. 2014, 9, e112071.

[44] Du, J.; Xie, J.; Yue, L., Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity. J Gen Physiol. 2009, 134, 471-488.

[45] Yang, W.; Zou, J.; Xia, R.; Vaal, M. L.; Seymour, V. A.; Luo, J.; Beech, D. J.; Jiang, L. H., State-dependent inhibition of TRPM2 channel by acidic pH. J Biol Chem. 2010, 285, 30411-30418.

[46] Xia, R.; Mei, Z. Z.; Mao, H. J.; Yang, W.; Dong, L.; Bradley, H.; Beech, D. J.; Jiang, L. H., Identification of pore residues engaged in determining divalent cationic permeation in transient receptor potential melastatin subtype channel 2. J Biol Chem. 2008, 283, 27426-27432.

[47] Mei, Z. Z.; Mao, H. J.; Jiang, L. H., Conserved cysteine residues in the pore region are obligatory for human TRPM2 channel function. Am J Physiol Cell Physiol. 2006, 291, 1022-1028.

[48] Kühn, F. J.; Knop, G.; Lückhoff, A., The transmembrane segment S6 determines cation versus anion selectivity of TRPM2 and TRPM8. J Biol Chem. 2007, 282, 27598-27609.

[49] Kim, T. K.; Nam, J. H.; Ahn, W. G.; Kim, N. H.; Ham, H. Y.; Hong, C. W.; Nam, J. S.; Lee, J.; Huh, S. O.; So, I.; Kim, S. J.; Song, D. K., Lys1110 of TRPM2 is critical for channel activation. Biochem J. 2013, 455, 319-327.

[50] Fliegert, R.; Watt, J. M.; Sch?bel, A.; Rozewitz, M. D.; Moreau, C.; Kirchberger, T.; Thomas, M. P.; Sick, W.; Araujo, A. C.; Harneit, A.; Potter, B. V. L.; Guse, A. H., Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349. Biochem J. 2017, 474, 2159-2175.

[51] Yu, P.; Liu, Z.; Yu, X.; Ye, P.; Liu, H.; Xue, X.; Yang, L.; Li, Z.; Wu, Y.; Fang, C.; Zhao, Y. J.; Yang, F.; Luo, J. H.; Jiang, L. H.; Zhang, L.; Zhang, L.; Yang, W., Direct Gating of the TRPM2 Channel by cADPR via Specific Interactions with the ADPR Binding Pocket. Cell Rep. 2019, 27, 3684-3695.

[52] Yu, P.; Xue, X.; Zhang, J.; Hu, X.; Wu, Y.; Jiang, L. H.; Jin, H.; Luo, J.; Zhang, L.; Liu, Z.; Yang, W., Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2. J Gen Physiol. 2017, 149, 219-235.

[53] Zhang, Z.; Tóth, B.; Szollosi, A.; Chen, J.; Csanády, L., Structure of a TRPM2 channel in complex with Ca(2+) explains unique gating regulation. Elife. 2018, 7, e15367.

[54] Huang, Y.; Winkler, P. A.; Sun, W.; Lü, W.; Du, J., Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium. Nature. 2018, 562, 145-149.

[55] Yin, Y.; Wu, M.; Hsu, A. L.; Borschel, W. F.; Borgnia, M. J.; Lander, G. C.; Lee, S. Y., Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel. Nat Commun. 2019, 10, 3740-3750.

[56] Wang, L.; Fu, T. M.; Zhou, Y.; Xia, S.; Greka, A.; Wu, H., Structures and gating mechanism of human TRPM2. Science. 2018, 362, 896-903.

[57] Kühn, F. J.; Kühn, C.; Winking, M.; Hoffmann, D. C.; Lückhoff, A., ADP-Ribose Activates the TRPM2 Channel from the Sea Anemone Nematostella vectensis Independently of the NUDT9H Domain. PLoS One. 2016, 11, e0158060.

[58] Kühn, F.; Kühn, C.; Lückhoff, A., Different Principles of ADP-Ribose-Mediated Activation and Opposite Roles of the NUDT9 Homology Domain in the TRPM2 Orthologs of Man and Sea Anemone. Front Physiol. 2017, 8, 879-886.

[59] Xia, S.; Wang, L.; Fu, T. M.; Wu, H., Mechanism of TRPM2 channel gating revealed by cryo-EM. Febs J. 2019, 286, 3333-3339.

[60] Huang, Y.; Fliegert, R.; Guse, A. H.; Lü, W.; Du, J., A structural overview of the ion channels of the TRPM family. Cell Calcium. 2020, 85, 102-111.

[61] Malko, P.; Jiang, L.-H., TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biol. 2020, 37, 755-765.

[62] Fonfria, E.; Marshall, I. C.; Boyfield, I.; Skaper, S. D.; Hughes, J. P.; Owen, D. E.; Zhang, W.; Miller, B. A.; Benham, C. D.; Mcnulty, S., Amyloid beta-peptide(1-42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. J Neurochem. 2005, 95, 715-723.

[63] Zhang, W.; Chu, X.; Tong, Q.; Cheung, J. Y.; Conrad, K.; Masker, K.; Miller, B. A., A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J Biol Chem. 2003, 278, 16222-16229.

[64] Fonfria, E.; Marshall, I. C.; Benham, C. D.; Boyfield, I.; Brown, J. D.; Hill, K.; Hughes, J. P.; Skaper, S. D.; Mcnulty, S., TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br J Pharmacol. 2004, 143, 186-192.

[65] Liu, M.; Tang, L.; Liu, X.; Fang, J.; Zhan, H.; Wu, H.; Yang, H., An Evidence-Based Review of Related Metabolites and Metabolic Network Research on Cerebral Ischemia. Oxid Med Cell Longev. 2016, 25, 916-924.

[66] Zuo, L.; Feng, Q.; Han, Y.; Chen, M.; Guo, M.; Liu, Z.; Cheng, Y.; Li, G., Therapeutic effect on experimental acute cerebral infarction is enhanced after nanoceria labeling of human umbilical cord mesenchymal stem cells. Ther Adv Neurol Disord. 2019, 12, 175-185.

[67] Ye, M.; Yang, W.; Ainscough, J. F.; Hu, X. P.; Li, X.; Sedo, A.; Zhang, X. H.; Zhang, X.; Chen, Z.; Li, X. M.; Beech, D. J.; Sivaprasadarao, A.; Luo, J. H.; Jiang, L. H., TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia. Cell Death Dis. 2014, 5, e1541.

[68] Jiang, Q.; Gao, Y.; Wang, C.; Tao, R.; Wu, Y.; Zhan, K.; Liao, M.; Lu, N.; Lu, Y.; Wilcox, C. S.; Luo, J.; Jiang, L. H.; Yang, W.; Han, F., Nitration of TRPM2 as a Molecular Switch Induces Autophagy During Brain Pericyte Injury. Antioxid Redox Signal. 2017, 27, 1297-1316.

[69] Miyake, T.; Shirakawa, H.; Kusano, A.; Sakimoto, S.; Konno, M.; Nakagawa, T.; Mori, Y.; Kaneko, S., TRPM2 contributes to LPS/IFNγ-induced production of nitric oxide via the p38/JNK pathway in microglia. Biochem Biophys Res Commun. 2014, 444, 212-217.

[70] Jia, J.; Verma, S.; Nakayama, S.; Quillinan, N.; Grafe, M. R.; Hurn, P. D.; Herson, P. S., Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke. J Cereb Blood Flow Metab. 2011, 31, 2160-2168.

[71] Alim, I.; Teves, L.; Li, R.; Mori, Y.; Tymianski, M., Modulation of NMDAR subunit expression by TRPM2 channels regulates neuronal vulnerability to ischemic cell death. J Neurosci. 2013, 33, 17264-17277.

[72] Zhan, K. Y.; Yu, P. L.; Liu, C. H.; Luo, J. H.; Yang, W., Detrimental or beneficial: the role of TRPM2 in ischemia/reperfusion injury. Acta Pharmacol Sin. 2016, 37, 4-12.

[73] Selkoe, D. J.; Hardy, J., The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016, 8, 595-608.

[74] Li, X.; Jiang, L. H., Multiple molecular mechanisms form a positive feedback loop driving amyloid β42 peptide-induced neurotoxicity via activation of the TRPM2 channel in hippocampal neurons. Cell Death Dis. 2018, 9, 195-207.

[75] Ostapchenko, V. G.; Chen, M.; Guzman, M. S.; Xie, Y. F.; Lavine, N.; Fan, J.; Beraldo, F. H.; Martyn, A. C.; Belrose, J. C.; Mori, Y.; Macdonald, J. F.; Prado, V. F.; Prado, M. A.; Jackson, M. F., The Transient Receptor Potential Melastatin 2 (TRPM2) Channel Contributes to β-Amyloid Oligomer-Related Neurotoxicity and Memory Impairment. J Neurosci. 2015, 35, 15157-15169.

[76] Pires, A. O.; Teixeira, F. G.; Mendes-Pinheiro, B.; Serra, S. C.; Sousa, N.; Salgado, A. J., Old and new challenges in Parkinson's disease therapeutics. Prog Neurobiol. 2017, 156, 69-89.

[77] Brudek, T., Inflammatory Bowel Diseases and Parkinson's Disease. J Parkinsons Dis. 2019, 9, 331-344.

[78] Hermosura, M. C.; Cui, A. M.; Go, R. C.; Davenport, B.; Shetler, C. M.; Heizer, J. W.; Schmitz, C.; Mocz, G.; Garruto, R. M.; Perraud, A. L., Altered functional properties of a TRPM2 variant in Guamanian ALS and PD. Proc Natl Acad Sci. 2008, 105, 18029-18034.

[79] Freestone, P. S.; Chung, K. K.; Guatteo, E.; Mercuri, N. B.; Nicholson, L. F.; Lipski, J., Acute action of rotenone on nigral dopaminergic neurons--involvement of reactive oxygen species and disruption of Ca2+ homeostasis. Eur J Neurosci. 2009, 30, 1849-1859.

[80] Sun, Y.; Sukumaran, P.; Selvaraj, S.; Cilz, N. I.; Schaar, A.; Lei, S.; Singh, B. B., TRPM2 Promotes Neurotoxin MPP(+)/MPTP-Induced Cell Death. Mol Neurobiol. 2018, 55, 409-420.

[81] Yu, P.; Cai, X.; Liang, Y.; Wang, M.; Yang, W., Roles of NAD(+) and Its Metabolites Regulated Calcium Channels in Cancer. Molecules. 2020, 25, 256-267.

[82] Hirschler-Laszkiewicz, I.; Chen, S. J.; Bao, L.; Wang, J.; Zhang, X. Q.; Shanmughapriya, S.; Keefer, K.; Madesh, M.; Cheung, J. Y.; Miller, B. A., The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation. Am J Physiol Cell Physiol. 2018, 315, 571-586.

[83] Cao, Q. F.; Qian, S. B.; Wang, N.; Zhang, L.; Wang, W. M.; Shen, H. B., TRPM2 mediates histone deacetylase inhibition-induced apoptosis in bladder cancer cells. Cancer Biother Radiopharm. 2015, 30, 87-93.

[84] Knowles, H.; Li, Y.; Perraud, A. L., The TRPM2 ion channel, an oxidative stress and metabolic sensor regulating innate immunity and inflammation. Immunol Res. 2013, 55, 241-248.

[85] Yamamoto, S.; Shimizu, S.; Kiyonaka, S.; Takahashi, N.; Wajima, T.; Hara, Y.; Negoro, T.; Hiroi, T.; Kiuchi, Y.; Okada, T.; Kaneko, S.; Lange, I.; Fleig, A.; Penner, R.; Nishi, M.; Takeshima, H.; Mori, Y., TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med. 2008, 14, 738-747.

[86] Syed Mortadza, S. A.; Wang, L.; Li, D.; Jiang, L.-H., TRPM2 Channel-Mediated ROS-Sensitive Ca(2+) Signaling Mechanisms in Immune Cells. Front Immunol. 2015, 6, 407-407.

[87] Wang, L.; Negro, R.; Wu, H., TRPM2, linking oxidative stress and Ca(2+) permeation to NLRP3 inflammasome activation. Curr Opin Immunol. 2020, 62, 131-135.

[88] S?zbir, E.; Naz?ro?lu, M., Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain. Metab Brain Dis. 2016, 31, 385-393.

[89] Uchida, K.; Tominaga, M., The role of TRPM2 in pancreatic β-cells and the development of diabetes. Cell Calcium. 2014, 56, 332-339.

[90] Togashi, K.; Hara, Y.; Tominaga, T.; Higashi, T.; Konishi, Y.; Mori, Y.; Tominaga, M., TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. Embo J. 2006, 25, 1804-1815.

[91] Kashio, M.; Tominaga, M., Redox Signal-mediated Enhancement of the Temperature Sensitivity of Transient Receptor Potential Melastatin 2 (TRPM2) Elevates Glucose-induced Insulin Secretion from Pancreatic Islets. J Biol Chem. 2015, 290, 12435-12442.

[92] Uchida, K.; Dezaki, K.; Damdindorj, B.; Inada, H.; Shiuchi, T.; Mori, Y.; Yada, T.; Minokoshi, Y.; Tominaga, M., Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice. Diabetes. 2011, 60, 119-126.

[93] Pang, B.; Kim, S.; Li, D.; Ma, Z.; Sun, B.; Zhang, X.; Wu, Z.; Chen, L., Glucagon-like peptide-1 potentiates glucose-stimulated insulin secretion via the transient receptor potential melastatin 2 channel. Exp Ther Med. 2017, 14, 5219-5227.

[94] Espinoza-Jiménez, A.; Peón, A. N.; Terrazas, L. I., Alternatively activated macrophages in types 1 and 2 diabetes. Mediators Inflamm. 2012, 2012, 815953.

[95] Li, F.; Munsey, T. S.; Sivaprasadarao, A., TRPM2-mediated rise in mitochondrial Zn(2+) promotes palmitate-induced mitochondrial fission and pancreatic β-cell death in rodents. Cell Death Differ. 2017, 24, 1999-2012.

[96] Zhang, Z.; Zhang, W.; Jung, D. Y.; Ko, H. J.; Lee, Y.; Friedline, R. H.; Lee, E.; Jun, J.; Ma, Z.; Kim, F.; Tsitsilianos, N.; Chapman, K.; Morrison, A.; Cooper, M. P.; Miller, B. A.; Kim, J. K., TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am J Physiol Endocrinol Metab. 2012, 302, 807-816.

[97] Song, K.; Wang, H.; Kamm, G. B.; Pohle, J.; Reis, F. C.; Heppenstall, P.; Wende, H.; Siemens, J., The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science. 2016, 353, 1393-1398.

[98] Morrison, S. F., Central neural control of thermoregulation and brown adipose tissue. Auton Neurosci. 2016, 196, 14-24.

[99] Kashio, M.; Tominaga, M., The TRPM2 channel: A thermo-sensitive metabolic sensor. Channels (Austin). 2017, 11, 426-433.

[100] Kamm, G. B.; Siemens, J., The TRPM2 channel in temperature detection and thermoregulation. Temperature (Austin). 2017, 4, 21-23.

[101] Tan, C. H.; Mcnaughton, P. A., The TRPM2 ion channel is required for sensitivity to warmth. Nature. 2016, 536, 460-463.

[102] Hill, K.; Benham, C. D.; Mcnulty, S.; Randall, A. D., Flufenamic acid is a pH-dependent antagonist of TRPM2 channels. Neuropharmacology. 2004, 47, 450-460.

[103] Chen, G. L.; Zeng, B.; Eastmond, S.; Elsenussi, S. E.; Boa, A. N.; Xu, S. Z., Pharmacological comparison of novel synthetic fenamate analogues with econazole and 2-APB on the inhibition of TRPM2 channels. Br J Pharmacol. 2012, 167, 1232-1243.

[104] Guinamard, R.; Simard, C.; Del Negro, C., Flufenamic acid as an ion channel modulator. Pharmacol Ther. 2013, 138, 272-284.

[105] Verma, S.; Quillinan, N.; Yang, Y. F.; Nakayama, S.; Cheng, J.; Kelley, M. H.; Herson, P. S., TRPM2 channel activation following in vitro ischemia contributes to male hippocampal cell death. Neurosci Lett. 2012, 530, 41-46.

[106] Jiang, H.; Zeng, B.; Chen, G. L.; Bot, D.; Eastmond, S.; Elsenussi, S. E.; Atkin, S. L.; Boa, A. N.; Xu, S. Z., Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels. Biochem Pharmacol. 2012, 83, 923-931.

[107] Hill, K.; Mcnulty, S.; Randall, A. D., Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole. N-S Arch Pharmacol. 2004, 370, 227-237.

[108] Meseguer, V.; Karashima, Y.; Talavera, K.; D'hoedt, D.; Donovan-Rodríguez, T.; Viana, F.; Nilius, B.; Voets, T., Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole. J Neurosci. 2008, 28, 576-586.

[109] Nilius, B.; Prenen, J.; Vennekens, R.; Hoenderop, J. G.; Bindels, R. J.; Droogmans, G., Pharmacological modulation of monovalent cation currents through the epithelial Ca2+ channel ECaC1. Br J Pharmacol. 2001, 134, 453-462.

[110] Malkia, A.; Pertusa, M.; Fernández-Ballester, G.; Ferrer-Montiel, A.; Viana, F., Differential role of the menthol-binding residue Y745 in the antagonism of thermally gated TRPM8 channels. Mol Pain. 2009, 5, 62-87.

[111] Kraft, R.; Grimm, C.; Frenzel, H.; Harteneck, C., Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl)anthranilic acid. Br J Pharmacol. 2006, 148, 264-273.

[112] Harteneck, C.; Frenzel, H.; Kraft, R., N-(p-amylcinnamoyl)anthranilic acid (ACA): a phospholipase A(2) inhibitor and TRP channel blocker. Cardiovasc Drug Rev. 2007, 25, 61-75.

[113] Delmas, P.; Wanaverbecq, N.; Abogadie, F. C.; Mistry, M.; Brown, D. A., Signaling microdomains define the specificity of receptor-mediated InsP(3) pathways in neurons. Neuron. 2002, 34, 209-220.

[114] Chung, M. K.; Lee, H.; Mizuno, A.; Suzuki, M.; Caterina, M. J., TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem. 2004, 279, 21569-21575.

[115] Hu, H. Z.; Gu, Q.; Wang, C.; Colton, C. K.; Tang, J.; Kinoshita-Kawada, M.; Lee, L. Y.; Wood, J. D.; Zhu, M. X., 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J Biol Chem. 2004, 279, 35741-35748.

[116] Xu, S. Z.; Zeng, F.; Boulay, G.; Grimm, C.; Harteneck, C.; Beech, D. J., Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol. 2005, 145, 405-414.

[117] Togashi, K.; Inada, H.; Tominaga, M., Inhibition of the transient receptor potential cation channel TRPM2 by 2-aminoethoxydiphenyl borate (2-APB). Br J Pharmacol. 2008, 153, 1324-1330.

[118] Moreau, C.; Kirchberger, T.; Swarbrick, J. M.; Bartlett, S. J.; Fliegert, R.; Yorgan, T.; Bauche, A.; Harneit, A.; Guse, A. H.; Potter, B. V., Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists. J Med Chem. 2013, 56, 10079-10102.

[119] Luo, X.; Li, M.; Zhan, K.; Yang, W.; Zhang, L.; Wang, K.; Yu, P.; Zhang, L., Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues. Chem Biol Drug Des. 2018, 91, 552-566.

[120] Cruz-Torres, I.; Backos, D. S.; Herson, P. S., Characterization and Optimization of the Novel Transient Receptor Potential Melastatin 2 Antagonist tatM2NX. Mol Pharmacol. 2020, 97, 102-111.

[121] Shimizu, T.; Dietz, R. M.; Cruz-Torres, I.; Strnad, F.; Garske, A. K.; Moreno, M.; Venna, V. R.; Quillinan, N.; Herson, P. S., Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia. Exp Neurol. 2016, 283, 151-156.

[122] Starkus, J. G.; Poerzgen, P.; Layugan, K.; Kawabata, K. G.; Goto, J. I.; Suzuki, S.; Myers, G.; Kelly, M.; Penner, R.; Fleig, A.; Horgen, F. D., Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels. J Nat Prod. 2017, 80, 2741-2750.

[123] Fourgeaud, L.; Dvorak, C.; Faouzi, M.; Starkus, J.; Sahdeo, S.; Wang, Q.; Lord, B.; Coate, H.; Taylor, N.; He, Y.; Qin, N.; Wickenden, A.; Carruthers, N.; Lovenberg, T. W.; Penner, R.; Bhattacharya, A., Pharmacology of JNJ-28583113: A novel TRPM2 antagonist. Eur J Pharmacol. 2019, 853, 299-307.

[124] Zhang, H.; Liu, H.; Luo, X.; Wang, Y.; Liu, Y.; Jin, H.; Liu, Z.; Yang, W.; Yu, P.; Zhang, L.; Zhang, L., Design, synthesis and biological activities of 2,3-dihydroquinazolin-4(1H)-one derivatives as TRPM2 inhibitors. Eur J Med Chem. 2018, 152, 235-252.

[125] Shimizu, T.; Macey, T. A.; Quillinan, N.; Klawitter, J.; Perraud, A. L.; Traystman, R. J.; Herson, P. S., Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury. J Cereb Blood Flow Metab. 2013, 33, 1549-1555.

[126] Nakayama, S.; Vest, R.; Traystman, R. J.; Herson, P. S., Sexually dimorphic response of TRPM2 inhibition following cardiac arrest-induced global cerebral ischemia in mice. J Mol Neurosci. 2013, 51, 92-98.

[127] Hiroi, T.; Wajima, T.; Negoro, T.; Ishii, M.; Nakano, Y.; Kiuchi, Y.; Mori, Y.; Shimizu, S., Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury. Cardiovasc Res. 2013, 97, 271-281.

[128] ?ak?r, M.; Tekin, S.; Ta?l?dere, A.; ?akan, P.; Düzova, H.; Gül, C. C., Protective effect of N-(p-amylcinnamoyl) anthranilic acid, phospholipase A(2) enzyme inhibitor, and transient receptor potential melastatin-2 channel blocker against renal ischemia-reperfusion injury. J Cell Biochem. 2019, 120, 3822-3832.

[129] Gelderblom, M.; Melzer, N.; Schattling, B.; G?b, E.; Hicking, G.; Arunachalam, P.; Bittner, S.; Ufer, F.; Herrmann, A. M.; Bernreuther, C.; Glatzel, M.; Gerloff, C.; Kleinschnitz, C.; Meuth, S. G.; Friese, M. A.; Magnus, T., Transient receptor potential melastatin subfamily member 2 cation channel regulates detrimental immune cell invasion in ischemic stroke. Stroke. 2014, 45, 3395-3402.

[130] Gao, M.; Du, Y.; Xie, J. W.; Xue, J.; Wang, Y. T.; Qin, L.; Ma, M. M.; Tang, Y. B.; Li, X. Y., Redox signal-mediated TRPM2 promotes Ang II-induced adipocyte insulin resistance via Ca(2+)-dependent CaMKII/JNK cascade. Metabolism. 2018, 85, 313-324.

[131] Cakir, M.; Duzova, H.; Tekin, S.; Tasl?dere, E.; Kaya, G. B.; Cigremis, Y.; Ozgocer, T.; Yologlu, S., ACA, an inhibitor phospholipases A2 and transient receptor potential melastatin-2 channels, attenuates okadaic acid induced neurodegeneration in rats. Life Sci. 2017, 176, 10-20.

[132] Gao, G.; Wang, W.; Tadagavadi, R. K.; Briley, N. E.; Love, M. I.; Miller, B. A.; Reeves, W. B., TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1. J Clin Invest. 2014, 124, 4989-5001.

[133] Thapak, P.; Bishnoi, M.; Sharma, S. S., Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study. Curr Neurovasc Res. 2020, 17, 249-258.

[134] Eraslan, E.; Tanyeli, A.; Polat, E.; Polat, E., 8-Br-cADPR, a TRPM2 ion channel antagonist, inhibits renal ischemia-reperfusion injury. J Cell Physiol. 2019, 234, 4572-4581.

[135] Dietz, R. M.; Cruz-Torres, I.; Orfila, J. E.; Patsos, O. P.; Shimizu, K.; Chalmers, N.; Deng, G.; Tiemeier, E.; Quillinan, N.; Herson, P. S., Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels. Transl Stroke Res. 2020, 11, 254-266.

[136] Wang, M.; Li, J.; Dong, S.; Cai, X.; Simaiti, A.; Yang, X.; Zhu, X.; Luo, J.; Jiang, L. H.; Du, B.; Yu, P.; Yang, W., Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction. Part Fibre Toxicol. 2020, 17, 23-32.

[137] Partida-Sanchez, S.; Gasser, A.; Fliegert, R.; Siebrands, C. C.; Dammermann, W.; Shi, G.; Mousseau, B. J.; Sumoza-Toledo, A.; Bhagat, H.; Walseth, T. F.; Guse, A. H.; Lund, F. E., Chemotaxis of mouse bone marrow neutrophils and dendritic cells is controlled by adp-ribose, the major product generated by the CD38 enzyme reaction. J Immunol. 2007, 179, 7827-7839.

[138] Baszczyňski, O.; Watt, J. M.; Rozewitz, M. D.; Guse, A. H.; Fliegert, R.; Potter, B. V. L., Synthesis of Terminal Ribose Analogues of Adenosine 5'-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2. J Org Chem. 2019, 84, 6143-6157.

[139] Baszczyňski, O.; Watt, J. M.; Rozewitz, M. D.; Fliegert, R.; Guse, A. H.; Potter, B. V. L., Synthesis of phosphonoacetate analogues of the second messenger adenosine 5'-diphosphate ribose (ADPR). RSC Adv. 2020, 10, 1776-1785.

[140] Kolisek, M.; Beck, A.; Fleig, A.; Penner, R., Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels. Mol Cell. 2005, 18, 61-69.

[141] Beck, A.; Kolisek, M.; Bagley, L. A.; Fleig, A.; Penner, R., Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes. Faseb J. 2006, 20, 962-964.

[142] Swarbrick, J. M.; Riley, A. M.; Mills, S. J.; Potter, B. V., Designer small molecules to target calcium signalling. Biochem Soc Trans. 2015, 43, 417-425.

[143] Rester, U., From virtuality to reality - Virtual screening in lead discovery and lead optimization: a medicinal chemistry perspective. Curr Opin Drug Discov Devel. 2008, 11, 559-568.

[144] Konrad, R. J.; Jolly, Y. C.; Major, C.; Wolf, B. A., Inhibition of phospholipase A2 and insulin secretion in pancreatic islets. Biochim Biophys Acta. 1992, 1135, 215-220.

[145] Olsen, H. L.; N?rby, P. L.; H?y, M.; Spee, P.; Thams, P.; Capito, K.; Petersen, J. S.; Gromada, J., Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism. Biochem Biophys Res Commun. 2003, 303, 1148-1151.

[146] Weil, A.; Moore, S. E.; Waite, N. J.; Randall, A.; Gunthorpe, M. J., Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8. Mol Pharmacol. 2005, 68, 518-527.

[147] Song, Y.; Buelow, B.; Perraud, A. L.; Scharenberg, A. M., Development and validation of a cell-based high-throughput screening assay for TRPM2 channel modulators. J Biomol Screen. 2008, 13, 54-61.

[148] Yu, P.; Li, J.; Jiang, J.; Zhao, Z.; Hui, Z.; Zhang, J.; Zheng, Y.; Ling, D.; Wang, L.; Jiang, L. H.; Luo, J.; Zhu, X.; Yang, W., A dual role of transient receptor potential melastatin 2 channel in cytotoxicity induced by silica nanoparticles. Sci Rep. 2015, 5, 18171.

[149] Zammit, S. C.; Cox, A. J.; Gow, R. M.; Zhang, Y.; Gilbert, R. E.; Krum, H.; Kelly, D. J.; Williams, S. J., Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates. Bioorg Med Chem Lett. 2009, 19, 7003-7006.

[150] Arai, Y.; Toda, M.; Miyamoto, T. Carboxamide derivative, its production and remedy containing said derivative. JP 60097946, 1985.

[151] Yedgar, S.; Cohen, Y.; Shoseyov, D., Control of phospholipase A2 activities for the treatment of inflammatory conditions. BBA-Mol Cell Biol L. 2006, 1761, 1373-1382.

[152] Scheuer, W., Phospholipase A2-regulation and inhibition. Wien Klin Wochenschr. 1989, 67, 153-159.

[153] Schiefer, I. T.; Vandevrede, L.; Fa’, M.; Arancio, O.; Thatcher, G. R. J., Furoxans (1,2,5-Oxadiazole-N-Oxides) as Novel NO Mimetic Neuroprotective and Procognitive Agents. J Med Chem. 2012, 55, 3076-3087.

[154] Wang, H. F.; Wang, Z. Q.; Ding, Y.; Piao, M. H.; Feng, C. S.; Chi, G. F.; Luo, Y. N.; Ge, P. F., Endoplasmic reticulum stress regulates oxygen-glucose deprivation-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS. CNS Neurosci Ther. 2018, 24, 29-38.

[155] Song, Y.; Li, M.; Li, J. C.; Wei, E. Q., Edaravone protects PC12 cells from ischemic-like injury via attenuating the damage to mitochondria. J Zhejiang Univ Sci B. 2006, 7, 749-756.

[156] Song, Y.; Bei, Y.; Xiao, Y.; Tong, H. D.; Wu, X. Q.; Chen, M. T., Edaravone, a free radical scavenger, protects neuronal cells' mitochondria from ischemia by inactivating another new critical factor of the 5-lipoxygenase pathway affecting the arachidonic acid metabolism. Brain Res. 2018, 1690, 96-104.

[157] Davis, C. K.; G, K. R., Postischemic supplementation of folic acid improves neuronal survival and regeneration in vitro. Nutr Res. 2020, 75, 1-14.

[158] Zhang, B.; Zhang, H. X.; Shi, S. T.; Bai, Y. L.; Zhe, X.; Zhang, S. J.; Li, Y. J., Interleukin-11 treatment protected against cerebral ischemia/reperfusion injury. Biomed Pharmacother. 2019, 115, 108816.

[159] Canela, M. D.; Pérez-Pérez, M. J.; Noppen, S.; Sáez-Calvo, G.; Díaz, J. F.; Camarasa, M. J.; Liekens, S.; Priego, E. M., Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach. J Med Chem. 2014, 57, 3924-3938.

[160] Leelananda, S. P.; Lindert, S., Computational methods in drug discovery. Beilstein J Org Chem. 2016, 12, 2694-2718.

[161] Nicholls, A.; Mcgaughey, G. B.; Sheridan, R. P.; Good, A. C.; Warren, G.; Mathieu, M.; Muchmore, S. W.; Brown, S. P.; Grant, J. A.; Haigh, J. A.; Nevins, N.; Jain, A. N.; Kelley, B., Molecular shape and medicinal chemistry: a perspective. J Med Chem. 2010, 53, 3862-3886.

[162] Li, M.; Jiang, J.; Yue, L., Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol. 2006, 127, 525-537.

[163] Dehnhard, D.; Kamke, D.; Kramer, P., Synthesis and Solid-State Structures of Alkyl-Substituted 3-Cyano-2-pyridones. Z Naturforsch B. 2004, 59, 1121-1131.

[164] Elansary, A. K.; Moneer, A. A.; Kadry, H. H.; Gedawy, E. M., Synthesis and antitumour activity of certain pyrido[2,3-d] pyrimidine and 1,8-naphthyridine derivatives. J Chem Res. 2014, 38, 578-596.

[165] Luo, T.; Yu, Q. 2-Oxadiazole-3-aminothieno[2,3-b]pyridine derivative useful in treatment of hepatitis C and its preparation. CN 106928250A, 2017.

[166] Bondavalli, F., An Efficient Synthesis of Functionalized 2-Pyridones by Direct Route or via Amide/Enolate Ammonium Salt Intermediates. Synthesis. 1999, 30, 1169-1174.

[167] Bindal, S.; Kumar, D.; Kommi, D. N.; Bhatiya, S.; Chakraborti, A. K., Efficient Organocatalytic Dual Activation Strategy for Preparing the Versatile Synthons (2E)-1-(Het)Aryl/styryl-3-(dimethylamino)prop-2-en-1-ones and α-(E)- [(Dimethylamino)methylene]cycloalkanones. Synthesis. 2011, 42, 1930-1935.

[168] Longa, E. Z.; Weinstein, P. R.; Carlson, S.; Cummins, R., Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989, 20, 84-91.