Structure-activity relationship of gramine derivatives in Ca2+ release from sarcoplasmic reticulum

5,6-Dibromo-1,2-dimethylgramine evoked Ca2+ release from skeletal muscle sa rcoplasmic reticulum through ryanodine receptors in a concentration-depende nt manner with an EC50 of 22.2 mu M. Since the EC50 of caffeine was 0.885 m M, 5,6-dibromo-1,2-dimethylgramine was 40 times more sensitive than caffein e. 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 effe ctive. Study of the structure-activity relationship for Ca2+ release indica ted that 1-methylation and/or both 5- and 6-bromination are important for C a2+ release. Thus, gramine derivatives are useful tools for the investigati on of Ca2+ release from sarcoplasmic reticulum. (C) 1999 Elsevier Science B .V. All rights reserved.