Structure–activity relationship of gramine derivatives in Ca 2+ release from sarcoplasmic reticulum

Abstract

5,6-Dibromo-1,2-dimethylgramine evoked Ca 2+ release from skeletal muscle sarcoplasmic reticulum through ryanodine receptors in a concentration-dependent manner with an EC 50 of 22.2 μM. Since the EC 50 of caffeine was 0.885 mM, 5,6-dibromo-1,2-dimethylgramine was 40 times more sensitive than caffeine. Among 14 gramine derivatives having different substituents at N-1, C-2, C-5 or C-6 of the indole skeleton, we found that five derivatives were effective. Study of the structure–activity relationship for Ca 2+ release indicated that 1-methylation and/or both 5- and 6-bromination are important for Ca 2+ release. Thus, gramine derivatives are useful tools for the investigation of Ca 2+ release from sarcoplasmic reticulum.