Dantrolene analogues revisited: general synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle

Bioorg Med Chem. 2003 Mar 6;11(5):663-73. doi: 10.1016/s0968-0896(02)00600-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Dantrolene / analogs & derivatives*
  • Dantrolene / chemical synthesis*
  • Dantrolene / pharmacology
  • In Vitro Techniques
  • Indicators and Reagents
  • Mice
  • Muscle Contraction / drug effects
  • Muscle Relaxants, Central / chemical synthesis*
  • Muscle Relaxants, Central / pharmacology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism*
  • Structure-Activity Relationship

Substances

  • Indicators and Reagents
  • Muscle Relaxants, Central
  • Dantrolene
  • Calcium