Structure-activity relationship of xanthines and skeletal muscle ryanodine receptor/Ca2+ release channel

Caffeine (1,3,7-trimethylxanthine) in the millimolar range is known to activate the skeletal muscle Ca2+ release channel (ryanodine receptor). Xanthine analogs substituted in the 1, 3, 7, 8 and 9 positions were tested for their capacity to increase [3H]ryanodine binding to skeletal muscle sarcoplasmic reticulum vesicles enriched in Ca2+ release activity and ryanodine receptor content. Of the 30 xanthines tested, 9 were more effective than caffeine in increasing [3H]ryanodine binding. The 7-methyl group of caffeine was most important for activating the ryanodine receptor, followed by the methyl groups in the 1 and 3 positions. An increase in hydrophobicity of the side chains in positions 7, 1 and 3 enhanced the ability of xanthines to activate the ryanodine receptor. Substitutions in positions 8 and 9 were without effect or were inhibitory. These results should help in developing xanthines specific for the sarcoplasmic reticulum Ca2+ release channel.