title: Structure-activity relationships for the Ca2+-releasing activity of 6-hydroxy-beta-carboline analogues in skeletal muscle sarcoplasmic reticulum-the effects of halogen substitution at C-5 and C-7.
abstract: This study of structure-activity relationships of 6-hydroxy-beta-carboline analogues has been performed on the basis of quantitative measurement of Ca2+-releasing activity in the sarcoplasmic reticulum of skinned fibres of skeletal muscle. Substitution of halogens for hydrogens at the C-5 and C-7 positions and further introduction of a methyl group into the N-9 position of 6-hydroxy-beta-carboline resulted in Ca2+-releasing activity. The 50% effective concentrations of 5,7-dibromoeudistomin D, 5,7-dichloroeudistomin D, 5,7-diiodoeudistomin D, 9-methyl-5,7-dibromoeudistomin D, 9-methyl-5,7-dichloroeudistomin D, 9-methyl-5,7-diiodoeudistomin D, and caffeine were 5.6 x 10(-6), 6.3 x 10(-6), 7.8 x 10(-6), 2.1 x 10(-6), 2.0 x 10(-5), 3.7 x 10(-5), and 4.7 x 10(-4) M, respectively, indicating that these analogues are 10-200 times more potent than caffeine. Substitution of bromine by chlorine or iodine at the C-5 and C-7 positions markedly reduced the activity of the analogues with a methyl group at the N-9 position. These results suggest that halogens at the C-5 and C-7 positions in the beta-carboline skeleton are essential for Ca2+-releasing activity and that an N-9 methyl group also affects the activity of these analogues. Thus, these 6-hydroxy-beta-carboline analogues might become powerful tools for studying the molecular mechanism of Ca2+ release in the sarcoplasmic reticulum.
authors.affiliation: Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Seino-Umeda
authors.forename: M
authors.initials: M
authors.lastname: Ishibashi
authors.forename: J
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohizumi
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006168:Guinea Pigs; D006219:Halogens / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; D000697:Central Nervous System Stimulants; D006219:Halogens; D002110:Caffeine; D002118:Calcium