STRUCTURE-ACTIVITY RELATIONSHIP OF BROMOEUDISTOMIN-D, A POWERFUL CA2-MUSCLE SARCOPLASMIC-RETICULUM( RELEASER IN SKELETAL)

Bromoeudistomin D and 9-methyl-7-bromoeudistomin D which have a beta-c arboline skeleton are powerful Ca2+ releasers from skeletal muscle sar coplasmic reticulum exhibiting caffeine-like properties. We examined t he effects of bromoeudistomin D analogues on Ca2+-induced Ca2+ release from skeletal muscle sarcoplasmic reticulum. Among bromoeudistomin D analogues, the Ca2+-releasing activities of carboline derivatives were higher than those of carbazole derivatives, suggesting that a carboli ne skeleton is significantly important for the manifestation of Ca2+-r eleasing activity and Ca2+ sensitivity of Ca2+-induced Ca2+ release. O n the contrary, the analogues which have a carbazole skeleton and brom ine at C-6 inhibit both Ca2+- and caffeine-induced Ca2+ release. 9-Met hyl-substitution of the analogue elevated its Ca2+-releasing activity. Moreover, there is a close correlation between the enhancement of [H- 3]ryanodine binding to sarcoplasmic reticulum by the analogues and the activation of Ca2+ release by them. Bromoudistomin D analogues may pr ovide valuable information about the structure-function relationship o f the ryanodine receptor/Ca2+ release channels in skeletal muscle sarc oplasmic reticulum.