Congenetic Hybrids Derived from Dearomatized Isoprenylated Acylphloroglucinol with Opposite Effects on Cav3.1 Low Voltage-Gated Ca2+ Channel

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.