The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both In Vitro and In Vivo

The transient receptor potential
melastatin 2 (TRPM2) channel is
associated with ischemia/reperfusion injury, inflammation, cancer,
and neurodegenerative diseases. However, the limit of specific inhibitors
impedes the development of TRPM2-targeted therapeutic agents. To discover
more potent and selective TRPM2 inhibitors, 59 N-(p-amylcinnamoyl) anthranilic acid (ACA) derivatives were
synthesized and evaluated using calcium imaging and electrophysiology
approaches. Systematic structure–activity relationship studies
resulted in some potent compounds inhibiting the TRPM2 channel with
sub-micromolar half-maximal inhibitory concentration values. Among
them, the preferred compound A23 exhibited TRPM2 selectivity
over TRPM8 and TRPV1 channels as well as phospholipase A2 and showed
neuroprotective activity in vitro. Following pharmacokinetic studies, A23 was further evaluated in a transient middle cerebral artery
occlusion model in vivo, which significantly reduced cerebral infarction.
These data indicate that A23 might serve as a useful
tool for TRPM2-related research as well as a lead compound for the
development of therapeutic agents for ischemic injury.

瞬态受体电位melastatin 2（TRPM2）通道与缺血/再灌注损伤、炎症、癌症及神经退行性疾病密切相关。然而，特异性抑制剂的限制阻碍了针对TRPM2的治疗性药物的研制。为发现更具活性和选择性的TRPM2抑制剂，研究人员合成了59种N-(对-阿米丁基肉桂酰)安替比林酸（ACA）衍生物，并利用钙成像和电生理学方法进行了评估。系统性的结构-活性关系研究导致了一些具有亚微摩尔半数最大抑制浓度的有效化合物抑制了TRPM2通道。其中，优选化合物A23在TRPM2选择性方面优于TRPM8和TRPV1通道，以及对磷脂酶A2的抑制，并在体外表现出神经保护活性。在药代动力学研究之后，A23在暂时性大脑中动脉闭塞模型中的体内评估进一步进行，显著减少了脑梗死。这些数据表明，A23可能成为TRPM2相关研究的有用工具，同时也是缺血损伤治疗药物开发的先导化合物。