title: Structure-activity relationship of bromoeudistomin D, a powerful Ca2+ releaser in skeletal muscle sarcoplasmic reticulum.
abstract: Bromoeudistomin D and 9-methyl-7-bromoeudistomin D which have a beta-carboline skeleton are powerful Ca2+ releasers from skeletal muscle sarcoplasmic reticulum exhibiting caffeine-like properties. We examined the effects of bromoeudistomin D analogues on Ca(2+)-induced Ca2+ release from skeletal muscle sarcoplasmic reticulum. Among bromoeudistomin D analogues, the Ca(2+)-releasing activities of carboline derivatives were higher than those of carbazole derivatives, suggesting that a carboline skeleton is significantly important for the manifestation of Ca(2+)-releasing activity and Ca2+ sensitivity of Ca(2+)-induced Ca2+ release. On the contrary, the analogues which have a carbazole skeleton and bromine at C-6 inhibit both Ca(2+)- and caffeine-induced Ca2+ release. 9-Methyl-substitution of the analogue elevated its Ca(2+)-releasing activity. Moreover, there is a close correlation between the enhancement of [3H]ryanodine binding to sarcoplasmic reticulum by the analogues and the activation of Ca2+ release by them. Bromoudistomin D analogues may provide valuable information about the structure-function relationship of the ryanodine receptor/Ca2+ release channels in skeletal muscle sarcoplasmic reticulum.
authors.affiliation: Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Furukawa
authors.forename: M
authors.initials: M
authors.lastname: Ishibashi
authors.forename: D
authors.initials: D
authors.lastname: Kozutsumi
authors.forename: H
authors.initials: H
authors.lastname: Ishiyama
authors.forename: J
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohizumi
mesh_terms: D000818:Animals; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002243:Carbolines / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D002243:Carbolines; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C048237:7-bromoeudistomine D; C060741:9-methyl-7-bromoeudistomin D; D002110:Caffeine; D002118:Calcium