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

• Published in: European journal of medicinal chemistry 2019-10, Vol.179, p.837-848
• Main Authors: Mori, Shuichi, Iinuma, Hiroto, Manaka, Noriaki, Ishigami-Yuasa, Mari, Murayama, Takashi, Nishijima, Yoshiaki, Sakurai, Akiko, Arai, Ryota, Kurebayashi, Nagomi, Sakurai, Takashi, Kagechika, Hiroyuki
• Format: Article
• Language: English
• Subjects: Calcium ion channel; Quinolone; Ryanodine receptor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.06.076

Type-1 ryanodine receptor (RyR1) 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 RyR1 are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyR1 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 RyR1 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 RyR1 channel inhibitors. [Display omitted] •Structural development of type-1 ryanodine receptor (RyR1) inhibitors was carried out based on the measurement of Ca2+ in ER.•Quinolone derivative 14h exhibited more potent RyR1 channel inhibitory activity than dantrolene, a known RyR1 inhibitor.•Synthesized quinolone derivatives exhibited high RyR1 selectivity over RyR2 and RyR3.•[3H]Ryanodine-binding assay suggested that the quinolines interacted with RyR1 directly to inhibit its channel activity.