Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative tode novodrug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients.

中文翻译：

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重新利用HAMI3379阻断GPR17并促进啮齿动物和人少突胶质细胞分化

查明现有药物的其他用途是药物发现中的热门话题，也是新药开发的可行替代方案。HAMI3379被称为半胱氨酰-白三烯CysLT2受体的拮抗剂，最初被开发用于治疗心血管疾病和炎性疾病。在我们的研究中，我们确定了HAMI3379是孤儿G蛋白偶联受体GPR17的拮抗剂。HAMI3379抑制重组人，大鼠和小鼠GPR17在各种细胞背景下的信号传导，以及在原代啮齿动物少突胶质细胞中的内源性GPR17信号传导。HAMI3379阻滞GPR17增强了原代大鼠和小鼠少突胶质细胞的成熟，但对GPR17基因敲除小鼠的少突胶质细胞没有作用。在由诱导性多能干细胞制备的人少突胶质细胞中，GPR17表达，其激活削弱少突胶质细胞的分化。相反，HAMI3379有效地促进了人类少突胶质细胞的分化。我们建议，HAMI3379有望用于孤儿GPR17的药理开发，以增强促进患者髓鞘再生的再生策略。