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•Diterpenoids including three kinds of rare skeletons were identified.•Diterpenoids with notable Cav3.1 inhibitory activities were initially discovered.•The ring at C-18 and C-19, and esterification of OH-17 with long-chain are the key features for Cav3.1 inhibition.
Seven new (1–4, 6–8) diterpenoids with rare skeletons and seven known ones (9, 12, 17, 18 and 23–25) were isolated from roasted beans of Coffea arabica L. Together with previously obtained diterpenoids, a total of 26 molecules (1–25, 4a) were evaluated their activities on Cav3.1 low voltage-gated Ca2+ channel. Compounds 1, 3, 6, 7, 12, 13, 17, 19 and 24 exhibited noticeable Cav3.1 inhibitions (41.2%-96.1%) at 10 μM. The IC50 values of 1, 6, 7, 12, 13, 17 and 24 are 2.9, 2.3, 0.68, 14.8, 11.6, 6.1 and 6.8 μM, respectively. The ring moiety at C-18 and C-19, and esterification of OH-17 with long-chain fatty acids seem important for their activities. Further studies indicated that 1 and cafestol may act on different binding sits with the Cav3.1 blocker Z944, which is in clinical trial. Significantly, the present study initially shows that coffee diterpenoids are potential natural resources for Cav3.1 inhibitors.