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 [H-3]ryanodine binding to skele tal muscle sarcoplasmic reticulum vesicles enriched in Ca2+ release ac tivity and ryanodine receptor content. Of the 30 xanthines tested, 9 w ere more effective than caffeine in increasing [H-3]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 posit ions. An increase in hydrophobicity of the side chains in positions 7, 1 and 3 enhanced the ability of xanthines to activate the ryanodine r eceptor. Substitutions in positions 8 and 9 were without effect or wer e inhibitory. These results should help in developing xanthines specif ic for the sarcoplasmic reticulum Ca2+ release channel.