Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels. (28th August 2018)

• Record Type: Journal Article
• Authors: Robinson, Ken; Easton, Christopher J.; Dulhunty, Angela F.; Casarotto, Marco G.
• Is Part Of: ChemMedChem. Volume 13:Number 18(2018)
• Page Start: 1957
• Page End: 1971
• Publication Date: 2018-08-28
• Subjects: calcium release -- muscle -- peptidomimetics -- ryanodine receptor -- scorpion toxins; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800366
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Ryanodine receptor (RyR) Ca 2+ ‐release channels are essential for contraction in skeletal and cardiac muscle and are prime targets for modification of contraction in disorders that affect either the skeletal or heart musculature. We designed and synthesized a number of compounds with structures based on a naturally occurring peptide (A peptides) that modifies the activity of RyRs. In total, 34 compounds belonging to eight different classes were prepared. The compounds were screened for their ability to enhance Ca 2+ release from isolated cardiac sarcoplasmic reticulum (SR) vesicles, with 25 displaying enhanced Ca 2+ release. Competition studies with the parent peptides indicated that the synthetic compounds act at a competing site. The activity of the most effective of the compounds, BIT 180, was further explored using Ca 2+ release from skeletal SR vesicles and contraction in intact skeletal muscle fibers. The compounds did not alter tension in intact fibers, indicating that (as expected) they are not membrane permeable, but importantly, that they are not toxic to the intact cells. Proof in principal that the compounds would be effective in intact muscle fibers if rendered membrane permeable was obtained with a structurally related membrane‐permeable scorpion toxin (imperatoxin A), which was found to enhance contraction. Abstract : Activating Ca 2+ release in muscle : Peptides derived from the dihydropyridine receptor have been previously identified as activators of ryanodine receptors (RyRs). By applying the principles of peptidomimetics, we synthesized a series of compounds that actively compete with these peptides to activate RyRs and initiate Ca 2+ release from calcium stores. These compounds may have a future role as probes for muscle function or as therapeutic compounds in muscle weakness.