Congenetic hybrids derived from dearomatized isoprenylated acylphloroglucinol with opposite effects on Ca v 3.1 low voltage-gated Ca 2+ 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 Ca2+ 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 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.