Gene

Biology

Fishery

Endocrinology

Malignant hyperthermia

Receptor

Telecommunications

Biochemistry

Skeletal muscle

Computer science

Endoplasmic reticulum

Anesthesia

Antibiotic resistance

RYR1

Ryanodine receptor

Oxolinic acid

Nalidixic acid

Antibiotics

Escherichia coli

Pharmacology

Medicine

Chemistry

Channel (broadcasting)

Biophysical Journal

Type 1 ryanodine receptor (RyR1) is a Ca2+ release channel on the sarcoplasmic reticulum in the skeletal muscle. Mutations in RyR1 cause various muscle diseases including malignant hyperthermia (MH) and central core disease (CCD). Although dantrolene is the only therapeutic drug for MH, it cannot be used for CCD due to its lower solubility and side effects. It is therefore urgent to discover novel RyR1 inhibitors. We have recently developed an efficient high-throughput screening platform for RyR1 inhibitors using Ca2+ measurements in the endoplasmic reticulum (ER). By screening a library of well-characterized drugs, we successfully identified oxolinic acid as a novel RyR1 inhibitor (Murayama et al., Mol Pharmacol, 94: 722-730, 2018). However, affinity of oxolinic acid was much lower than that of dantrolene. In this study, we designed and synthesized a series of quinolone derivatives using oxolinic acid as a lead compound. Dose-dependent inhibitory effects were evaluated by ER Ca2+ measurement using HEK293 cells expressing R-CEPIA1er, a genetically-encoded EC Ca2+ indicator, and RyR1 carrying an MH mutation (R2163C). Compounds bearing a longer alkyl chain at the nitrogen atom of quinolone ring exhibited stronger RyR1 inhibiting activity. Modification at 6 and 7 positions of quinolone ring greatly affected the inhibitory activity. The most potent derivative so far exhibited >50 and 4-fold greater affinity than oxolinic acid and dantrolene, respectively. These compounds may be good candidates for treatment of RyR1-related diseases.

Structure Development of Oxolinic Acid, a Novel Inhibitor of Type 1 Ryanodine Receptor (RyR1) Ca2+ Release Channel