Synthesis of Pseudellone Analogs and Characterization as Novel T-type Calcium Channel Blockers

T-type calcium channel (Cav3.x) blockers are receiving increasing attention as potential therapeutics for the treatment of pathophysiological disorders and diseases, including absence epilepsy, Parkinson’s disease (PD), hypertension, cardiovascular diseases, cancers, and pain. However, few clinically approved Cav3.x blockers are available, and selective pharmacological tools are needed to further unravel the roles of individual Cav3.x subtypes. In this work, through an efficient synthetic route to the marine fungal product pseudellone C, we obtained bisindole alkaloid analogs of pseudellone C with a modified tryptophan moiety and identified two Cav3.2 (2, IC50 = 18.24 µM; 3, IC50 = 6.59 µM) and Cav3.3 (2, IC50 = 7.71 µM; 3, IC50 = 3.81 µM) selective blockers using a FLIPR cell-based assay measuring Cav3.x window currents. Further characterization by whole-cell patch-clamp revealed a preferential block of Cav3.1 activated current (2, IC50 = 5.60 µM; 3, IC50 = 9.91 µM), suggesting their state-dependent block is subtype specific.