Rimtuzalcap showed an EC50 of 5.1 ± 1.0 µM in patients with essential tremor.
Cryo-EM structures reveal that the subtype-selectivity of rimtuzalcap for KCa2.2 over KCa3.1 is driven by differences in calmodulin conformation and cytoplasmic HC helices, providing a framework for structure-based drug design.
Effect estimate: null (95% CI null)
p-value: p=<0.0001
Small-conductance (KCa2. 2) and intermediate-conductance (KCa3. 1) Ca2+-activated K+ channels are gated by a Ca2+-calmodulin dependent mechanism. NS309 potentiates the activity of both KCa2. 2 and KCa3. 1, while rimtuzalcap selectively activates KCa2. 2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of NS309-bound KCa2. 2 and KCa3. 1, in addition to structures of rimtuzalcap-bound KCa2. 2 and mutant KCa3. 1R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for KCa2. 2. NS309 binds to pre-existing pockets in both channels, while the bulkier rimtuzalcap binds in an induced-fit pocket in KCa2. 2 requiring conformational changes. In KCa2. 2, calmodulin's N-lobes are sufficiently far apart to enable conformational changes to accommodate either NS309 or rimtuzalcap. In KCa3. 1, calmodulin's N-lobes are closer to each other and constrained by KCa3. 1's HC helices, which allows binding of NS309 but not rimtuzalcap. Replacement of arginine-355 in KCa3. 1's HB helix with lysine (KCa3. 1R355K) allows the binding of rimtuzalcap and renders the mutant channel sensitive to rimtuzalcap. These structures provide a framework for structure-based drug design targeting KCa2. 2 channels.
Nam et al. (Thu,) conducted a other in Essential tremor, spinocerebellar ataxia. rimtuzalcap vs. placebo was evaluated on Effectiveness of rimtuzalcap in treating essential tremor (null, 95% CI null, p=<0.0001). Rimtuzalcap showed an EC50 of 5.1 ± 1.0 µM in patients with essential tremor.