1,2- seco -Bicyclic Polyprenylated Acylphloroglucinols as Isoform Selective Inhibitors of T-Type Calcium Channels

Hyreptaones A–E (1–5, respectively), five undescribed 1,2-seco-bicyclic polyprenylated acylphloroglucinols (BPAPs), were discovered in Hypericum reptans. 1–3 constitute the first 1,2-seco-BPAPs originating from rare 3,3-diisoprenylated BPAPs. 4 and 5 possess a spirocyclic 6/5/5 scaffold arising from further cyclization of 1,2-seco-BPAP. Their structures were determined by spectroscopic analysis and X-ray crystallography. 1–5 preferentially inhibited Cav3.1 over other T-type calcium channels, whereas 4 and 5 exhibited state-dependent gating modulation of Cav3.1 and represent a novel class of Cav3.1 allosteric modulators.