Discovery of α-Obscurine Derivatives as Novel Ca v 3.1 Calcium Channel Blockers.

Voltage-gated calcium channels (VGCCs), particularly T-type calcium channels (TTCCs), are crucial for various physiological processes and have been implicated in pain, epilepsy, and cancer. Despite the clinical trials of TTCC blockers like Z944 and MK8998, none are currently available on the market. This study investigates the efficacy of Lycopodium alkaloids, particularly as natural product-based TTCC blockers. We synthesized eighteen derivatives from α-obscurine, a lycodine-type alkaloid, and identified five derivatives with significant Ca v 3.1 blockade activity. The most potent derivative, compound 7, exhibited an IC 50 value of 0.19±0.03 μM and was further analyzed through molecular docking, revealing key interactions with Ca v 3.1. These findings provide a foundation for the structural optimization of Ca v 3.1 calcium channel blockers and present compound 7 as a promising lead compound for drug development and a tool for chemical biology research.