Novel Plant Metabolites Show Isoform-Selective Inhibition of Cav3.1 Calcium Channels
- Five new natural products, hyreptaones A-E (1-5), were isolated from the plant Hypericum reptans, defining a novel class of 1,2-seco-bicyclic polyprenylated acylphloroglucinols (BPAPs).
- Compounds 1-3 are the first 1,2-seco-BPAPs shown to derive from rare 3,3-diisoprenylated BPAP precursors, while 4 and 5 feature an unusual spirocyclic 6/5/5 ring system formed by further cyclization of the 1,2-seco-BPAP core.
- Structures were established using spectroscopic analysis together with X-ray crystallography.
- All five compounds preferentially inhibited the Cav3.1 T-type calcium channel over other T-type channel subtypes, indicating isoform selectivity.
- Compounds 4 and 5 additionally showed state-dependent modulation of Cav3.1 gating, marking them as a new class of Cav3.1 allosteric modulators.
Isoform selectivity within the T-type family (Cav3.1 vs 3.2/3.3) is exactly what's been missing from this space — most T-type blockers I've seen are promiscuous pore-blockers with narrow therapeutic windows, so five compounds hitting Cav3.1 preferentially is worth a second look. The state-dependent gating modulation in 4/5 is the more interesting story mechanistically: allosteric, conformation-selective action tends to buy better selectivity and fewer off-target liabilities than brute-force channel block. That said, I'm skeptical this scaffold is a med-chem starting point rather than a probe — a spirocyclic 6/5/5 BPAP that needed X-ray to nail down stereochemistry screams synthetic bottleneck, and five compounds isolated from one plant is not a supply chain, it's a bottleneck waiting to happen. I'd want SAR against simplified, truncated analogs before believing this is optimizable rather than just interesting.