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 Cav3.1 low voltage-gated Ca2+ channel, with 1 and 4, respectively, being the most potent Cav3.1 agonist and antagonist from natural products. Further studies suggest that compound 1 and its biogenetical precursor, 2, have the same binding site on Cav3.1 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 Cav3.1 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 Cav3.1 physiology and pathophysiology, as well as afford possible leads for developing new drugs against SCA42, epilepsy, and pain.

中文翻译：

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衍生自脱芳香化的异戊二酰化酰基间苯三酚的同系杂种，对Cav3.1低压门控Ca2 +通道具有相反的作用。

从金丝桃属植物中鉴定出脱芳香化的异戊烯基化的酰基间苯三酚（DIAP）和单萜类化合物，pat酮A（1）及其生物合成类似物2-4的杂种。结构上，1具有空前的螺[双环[3.2.1]辛烷-6,1'-环己基] -2'，4'，6'-三酮核，其通过广泛的光谱学和X射线晶体学分析得以阐明。生物学研究表明，化合物1和2-4对Cav3.1低压门控Ca2 +通道产生相反的影响，化合物1和4分别是天然产物中最有效的Cav3.1激动剂和拮抗剂。进一步的研究表明，化合物1及其生物遗传前体2在Cav3.1上具有相同的结合位点，并且C-5和C-6处的刚性笼状部分是导致1成为激动剂的关键结构特征。此外，1可以使在脊髓小脑性共济失调42（SCA42）中发现的突变Cav3.1通道的病理门控正常化，这是一种遗传性神经退行性疾病，尚无可用疗法。总的来说，我们的发现为将来的Cav3.1生理学和病理生理学研究提供了有价值的工具，并为开发针对SCA42，癫痫和疼痛的新药提供了可能的线索。