Dantrolene analogues revisited: general synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle.
The general synthesis of dantrolene analogues with various substituents on its phenyl ring has been developed via palladium-catalyzed cross-coupling reactions, the Stille or Suzuki reaction, as the key step. The effects of synthesized analogues have been evaluated by two kinds of Ca(2+) release modes from sarcoplasmic reticulum (SR) of mouse skeletal muscle fibers based on: (1) the measurement of twitch contraction caused by the physiological Ca(2+) release (PCR) of intact skeletal muscle and (2) the rate of Ca(2+)-induced Ca(2+) release (CICR) in saponin-treated skinned muscle fibers. Although dantrolene, a lead compound, inhibits both twitch contraction and CICR, some structurally modified analogues exhibit one or the other of these effects. The methoxy congener, GIF-0185, potently inhibits the twitch contraction without affecting the CICR, while GIF-0166 and GIF-0248, the ortho-nitro regioisomer and ortho, ortho-dinitro substituted analogues, respectively, doubly potentiate the CICR exclusively.
Hosoya
Takamitsu
T
Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan.
Aoyama
Hiroshi
H
Ikemoto
Takaaki
T
Kihara
Yasutaka
Y
Hiramatsu
Toshiyuki
T
Endo
Makoto
M
Suzuki
Masaaki
M
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D003620:Dantrolene / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000138:chemical synthesis* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D009125:Muscle Relaxants, Central; D003620:Dantrolene; D002118:Calcium