Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay
- Eur J Med Chem. 2019 Oct 1:179:837-848. doi: 10.1016/j.ejmech.2019.06.076.
- 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, 101-0062, Japan.
- 2. Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
- 3. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, 101-0062, Japan. Electronic address: [email protected].
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.