AbstractRyanodine receptor (RyR) Ca2+‐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 Ca2+ release from isolated cardiac sarcoplasmic reticulum (SR) vesicles, with 25 displaying enhanced Ca2+ 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 Ca2+ 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.