Structure-activity relationship of gramine derivatives in Ca(2+) release from sarcoplasmic reticulum.
5,6-Dibromo-1,2-dimethylgramine evoked Ca(2+) release from skeletal muscle sarcoplasmic reticulum through ryanodine receptors in a concentration-dependent manner with an EC(50) of 22.2 microM. Since the EC(50) of caffeine was 0.885 mM, 5,6-dibromo-1,2-dimethylgramine was 40 times more sensitive than caffeine. Among 14 gramine derivatives having different substituents at N-1, C-2, C-5 or C-6 of the indole skeleton, we found that five derivatives were effective. Study of the structure-activity relationship for Ca(2+) release indicated that 1-methylation and/or both 5- and 6-bromination are important for Ca(2+) release. Thus, gramine derivatives are useful tools for the investigation of Ca(2+) release from sarcoplasmic reticulum.
Nakahata
N
N
Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan. nakahata@mail.pharm.tohoku.ac.jp
Harada
Y
Y
Tsuji
M
M
Kon-ya
K
K
Shizuri
Y
Y
Ohizumi
Y
Y
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D026121:Indole Alkaloids; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
D000470:Alkaloids; D026121:Indole Alkaloids; D014316:Tritium; D012433:Ryanodine; D002110:Caffeine; C007884:gramine; D002118:Calcium