Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay

被引：15

作者：

Mori, Shuichi ^{[1
]}

Iinuma, Hiroto ^{[1
]}

Manaka, Noriaki ^{[1
]}

Ishigami-Yuasa, Mari ^{[1
]}

Murayama, Takashi ^{[2
]}

Nishijima, Yoshiaki ^{[2
]}

Sakurai, Akiko ^{[2
]}

Arai, Ryota ^{[2
]}

Kurebayashi, Nagomi ^{[2
]}

Sakurai, Takashi ^{[2
]}

Kagechika, Hiroyuki ^{[1
]}

机构：

[1] TMDU, Inst Biomat & Bioengn, Tokyo 1010062, Japan

[2] Juntendo Univ, Grad Sch Med, Dept Cellular & Mol Pharmacol, Tokyo 1138421, Japan

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 179卷

关键词：

Ryanodine receptor; Quinolone; Calcium ion channel; RELEASE CHANNELS; MALIGNANT HYPERTHERMIA; DANTROLENE INHIBITION; MECHANISM;

D O I：

10.1016/j.ejmech.2019.06.076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Type-1 ryanodine receptor (RyRI) is a calcium-release channel localized on sarcoplasmic reticulum (SR) of the skeletal muscle, and mediates muscle contraction by releasing Ca2+ from the SR. Genetic mutations of RyRI are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyRI causes leakage of Ca2+ from the SR. We recently developed an efficient high-throughput screening system based on the measurement of Ca2+ in endoplasmic reticulum, and used it to identify oxolinic acid (1) as a novel RyRI channel inhibitor. Here, we designed and synthesized a series of quinolone derivatives based on 1 as a lead compound. Derivatives bearing a long alkyl chain at the nitrogen atom of the quinolone ring and having a suitable substituent at the 7-position of quinolone exhibited potent RyR1 channel-inhibitory activity. Among the synthesized compounds, 14h showed more potent activity than dantrolene, a known RyR1 inhibitor, and exhibited high RyR1 selectivity over RyR2 and RyR3. These compounds may be promising leads for clinically applicable RyRI channel inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页码：837 / 848

页数：12

共 26 条

[1] Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle [J].