Structure development of oxolinic acid, a novel inhibitor of type 1 ryanodine receptor

Abstract

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 drugs 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 identified oxolinic acid as a novel RyR1 inhibitor. 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 ER 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. Derivatives of oxolinic acid may be good candidates for treatment of RyR1-related diseases.