Discovery of α‐Obscurine Derivatives as Novel Cav3.1 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....

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Bibliographic Details
Published in:Chemistry & biodiversity 2024-04, Vol.21 (4), p.e202400182-n/a
Main Authors: Wang, Lei, Li, Wen‐Yan, Yuan, Zai‐Feng, Zhao, Qin‐Shi
Format: Article
Language:English
Subjects:
Alkaloids
Calcium channel blockers
Calcium channels
Calcium channels (voltage-gated)
Calcium compounds
Cav3.1 Lycopodium alkaloids
Channels
Clinical trials
Drug development
Epilepsy
Lead compounds
Molecular docking
Natural products
T-type calcium channels
Voltage-gated calcium channels
α-obscurine
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Summary: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 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.
ISSN:1612-1872
1612-1880
DOI:10.1002/cbdv.202400182