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Five caged polycyclic polyprenylated acylphloroglucinols including an unprecedented octahydro-2,5-methanoindene skeleton (1) were discovered from Hypericum curvisepalum. Biologically, 1 and 2 are potent Cav3.2 T-type Ca2+ channel inhibitors with negligible effect on the cardiovascular antitarget, the human ether-à-go-go-related gene potassium channel. Additionally, 2 indicates strong antinociception in the mouse acetic acid writhing test. [ABSTRACT FROM AUTHOR]

Hypulatones A and B ( 1 and 2 ), two racemic meroterpenoids possessing an unprecedented spiro[benzofuran-2,1'-cycloundecan]-4'-ene-4,6(5 H )-dione core, were characterized from Hypericum patulum . Compound 2 was found to significantly inhibit the late current of Na v 1.5 (late I Na , IC 50 = 0.2 μM). Importantly, 2 exhibited remarkable separation (>100-fold) of late I Na relative to peak I Na and notable selectivity over Ca v 3.1, K v 1.5, and hERG. 1 showed comparable inhibition on late I Na compared to that of 2 with poorer selectivity.

A hybrid of dearomatized isoprenylated acylphloroglucinol (DIAP) and monoterpenoid, hypatone A ( 1 ), together with its biosynthetic analogues 2 - 4 is characterized from Hypericum patulum . Structurally, 1 possesses an unprecedented spiro[bicyclo[3.2.1]octane-6,1'-cyclohexan]-2',4',6'-trione core as elucidated by extensive spectroscopic and X-ray crystallographic analyses. Biological studies reveal that compounds 1 and 2 - 4 produce opposite effects on Ca v 3.1 low voltage-gated Ca 2+ channel, with 1 and 4 , respectively, being the most potent Ca v 3.1 agonist and antagonist from natural products. Further studies suggest that compound 1 and its biogenetical precursor, 2 , have the same binding site on Ca v 3.1 and that the rigid cagelike moiety at C-5 and C-6 is a key structural feature responsible for 1 being an agonist. Furthermore, 1 can normalize the pathological gating of a mutant Ca v 3.1 channel found in spinocerebellar ataxia 42 (SCA42), a hereditary neurodegenerative disorder with no available therapy. Collectively, our findings provide valuable tools for future studies on Ca v 3.1 physiology and pathophysiology, as well as afford possible leads for developing new drugs against SCA42, epilepsy, and pain.