Development of a water-soluble ryanodine receptor 1 inhibitor
Development of a water-soluble ryanodine receptor 1 inhibitor
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水溶性兰尼定受体1抑制剂的开发
DOI：
10.1016/j.bmc.2022.117027
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kagechika Hiroyuki
中科院分区：
文献类型：
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作者：
Ishida Ryosuke;Mori Shuichi;Murayama Takashi;Nakamichi Ayaka;Chai Xikun;Kurebayashi Nagomi;Iinuma Hiroto;Kagechika Hiroyuki
Ryanodine receptor 1（RyR 1）是肌浆网（SR）膜上表达的钙释放通道。RyR 1介导Ca 2+从SR释放到细胞质以诱导肌肉收缩，与RyR 1过度激活相关的突变导致致命的肌肉疾病。丹曲林钠盐（dantrolene Na）是唯一批准用于治疗具有RyR 1突变的恶性高热患者的RyR抑制剂，但水溶性差。我们的小组最近开发了一个生物测定系统，并使用它来确定喹啉衍生物，如1作为有效的RyR 1抑制剂。在本研究中，我们专注于这些抑制剂的改性，目的是增加其水溶性。首先，我们尝试通过缩短1的喹诺酮环上的N-辛基链来降低疏水性; N-庚基化合物保留了RyR 1抑制活性，但N-己基化合物显示出降低的活性。接下来，我们引入了一个亲水性更强的azaquinolone环来代替喹诺酮;在这种情况下，只有N-辛基化合物保留了活性。N-辛基氮喹啉酮7的钠盐显示出与丹曲林钠相似的抑制活性，在盐水中的溶解度约为1，000倍。
Ryanodine receptor 1 (RyR1) is a Ca2+-release channel expressed on the sarcoplasmic reticulum (SR) membrane. RyR1 mediates release of Ca2+from the SR to the cytoplasm to induce muscle contraction, and mutations associated with overactivation of RyR1 cause lethal muscle diseases. Dantrolene sodium salt (dantrolene Na) is the only approved RyR inhibitor to treat malignant hyperthermia patients with RyR1 mutations, but is poorly water-soluble. Our group recently developed a bioassay system and used it to identify quinoline derivatives such as1as potent RyR1 inhibitors. In the present study, we focused on modification of these inhibitors with the aim of increasing their water-solubility. First, we tried reducing the hydrophobicity by shortening theN-octyl chain at the quinolone ring of1; theN-heptyl compound retained RyR1-inhibitory activity, but theN-hexyl compound showed decreased activity. Next, we introduced a more hydrophilic azaquinolone ring in place of quinolone; in this case, only theN-octyl compound retained activity. The sodium salt ofN-octyl azaquinolone7showed similar inhibitory activity to dantrolene Na with approximately 1,000-fold greater solubility in saline.