A hybrid of dearomatized isoprenylated acylphloroglucinol (DIAP) and monoterpenoid, hypatone A (), together with its biosynthetic analogues - is characterized from . Structurally, 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 and - produce opposite effects on Ca3.1 low voltage-gated Ca channel, with and , respectively, being the most potent Ca3.1 agonist and antagonist from natural products. Further studies suggest that compound and its biogenetical precursor, , have the same binding site on Ca3.1 and that the rigid cagelike moiety at C-5 and C-6 is a key structural feature responsible for being an agonist. Furthermore, can normalize the pathological gating of a mutant Ca3.1 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 Ca3.1 physiology and pathophysiology, as well as afford possible leads for developing new drugs against SCA42, epilepsy, and pain.
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