Design of dantrolene-derived probes for radioisotope-free photoaffinity labeling of proteins involved in the physiological Ca2+ release from sarcoplasmic reticulum of skeletal muscle

Bioorg Med Chem Lett. 2005 Mar 1;15(5):1289-94. doi: 10.1016/j.bmcl.2005.01.041.

Abstract

Bifunctional dantrolene derivatives have been synthesized as probes for radioisotope-free photoaffinity labeling with the aim of elucidating the molecular mechanism of skeletal muscle contraction. GIF-0430 and GIF-0665 are aromatic azido-functionalized derivatives that were designed to selectively inhibit physiological Ca2+ release (PCR) from sarcoplasmic reticulum (SR) in mouse skeletal muscle without a strong effect on Ca2+-induced Ca2+ release (CICR). These photoaffinity probes consist of either an azidomethyl or an ethynyl group, respectively, which could function as a tag for introduction of an optional detectable marker unit by an appropriate chemoselective ligation method after the photo-cross-linking operation. Actually, the former probe worked to photolabel its target proteins specifically as confirmed by subsequent fluorescent visualization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Dantrolene / analogs & derivatives*
  • Dantrolene / chemical synthesis*
  • Dantrolene / chemistry
  • Dantrolene / pharmacology
  • Drug Design
  • In Vitro Techniques
  • Mice
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Photoaffinity Labels / chemical synthesis*
  • Photoaffinity Labels / pharmacology
  • Photochemistry
  • Proteins / drug effects
  • Proteins / metabolism*
  • Sarcoplasmic Reticulum / metabolism*
  • Sensitivity and Specificity

Substances

  • GIF-0162
  • GIF-0373
  • GIF-0430
  • GIF-0667
  • Photoaffinity Labels
  • Proteins
  • Dantrolene
  • Calcium