Affiliation:
1. State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of Botany Chinese Academy of Sciences Kunming 650201 China
2. University of Chinese Academy of Sciences Beijing 100049 China
Abstract
AbstractVoltage‐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 Cav3.1 blockade activity. The most potent derivative, compound 7, exhibited an IC50 value of 0.19±0.03 μM and was further analyzed through molecular docking, revealing key interactions with Cav3.1. These findings provide a foundation for the structural optimization of Cav3.1 calcium channel blockers and present compound 7 as a promising lead compound for drug development and a tool for chemical biology research.
Funder
National Natural Science Foundation of China
Yunnan Provincial Science and Technology Department