Congenetic Hybrids Derived from Dearomatized Isoprenylated Acylphloroglucinol with Opposite Effects on Ca_v3.1 Low Voltage-Gated Ca²⁺ Channel

Abstract

A hybrid of dearomatized isoprenylated acylphloroglucinol (DIAP) and monoterpenoid, hypatone A (<b>1</b>), together with its biosynthetic analogues <b>2</b>-<b>4</b> is characterized from <i>Hypericum patulum</i>. Structurally, <b>1</b> 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 <b>1</b> and <b>2</b>-<b>4</b> produce opposite effects on Ca_v3.1 low voltage-gated Ca²⁺ channel, with <b>1</b> and <b>4</b>, respectively, being the most potent Ca_v3.1 agonist and antagonist from natural products. Further studies suggest that compound <b>1</b> and its biogenetical precursor, <b>2</b>, have the same binding site on Ca_v3.1 and that the rigid cagelike moiety at C-5 and C-6 is a key structural feature responsible for <b>1</b> being an agonist. Furthermore, <b>1</b> can normalize the pathological gating of a mutant Ca_v3.1 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_v3.1 physiology and pathophysiology, as well as afford possible leads for developing new drugs against SCA42, epilepsy, and pain.