Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders

Ryanodine receptors (RyRs) are intracellular Ca²⁺ channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca²⁺. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.