知母皂苷体内代谢及代谢产物与抗抑郁活性关系研究

Steroidal saponins are the main active compounds of Rhizoma Anemarrhenae. In previous studies, our team found that two types of steroidal sapnins (spirostanol saponins and furostanol saponins) of R. Anemarrhenae had showed the pronounced antidepressant pharmacological activity. Two common metabolites (M1 and M5, all ascribed to furostanol saponins) were detected in rat's brain after adminstration of two types of steroidal sapnins. Furthermore, the novel metabolite M10 was found in rat's brain after adminstration of furostanol saponins (the chemical structure of M10 was achieved by artificial preparation and also ascribed to furostanol saponins), while new structure was unfound in rat's brain after adminstration of spirostanol saponins. The specific mechanism is still unclear..This application will to study throughly on the absorption, distribution, metabolism, excretion and the metabolites, especially for the metabolites on the encephalic region of rats, to preparate artificially the main metabolites (especially for the new chemical structures), to find the compounds with the most pronounced activity as well as the pharmacological screening of antidepressant. The relationships of metabolism, metabolites and pharmacological activities are to clarify, the direct pharmacodynamic materials in vivo of R. Anemarrhenae are to reveal. Our researches will provide a scientific basis for new drugs and lead compounds and a useful reference for the similar researches.

皂苷类成分为中药知母的主要活性物质。本团队前期研究发现：知母所含的螺甾烷型和呋甾烷型两种结构类型皂苷均具有明显的抗抑郁药理活性。还发现动物分别给予这两类皂苷后，在脑区中都检测到两种共同的代谢产物（M1和M5，均属呋甾皂苷结构）。此外，给予呋甾皂苷后脑区中发现新结构的代谢产物M10（经人工制备后确证了结构，属呋甾烷型皂苷），而螺甾皂苷给药后脑区中未发现该新结构。具体机制尚不清楚。.本申请项目将系统研究几种典型知母皂苷单体成分（分属螺甾烷型和呋甾烷型）在动物体内的吸收、分布、代谢、排泄及代谢产物，尤其脑区中的代谢产物，并人工制备部分代谢产物（尤其新结构），结合抗抑郁药理筛选，寻找具有明显活性的化合物。阐明知母皂苷体内代谢及代谢产物与药理活性的关系，为揭示知母抗抑郁体内直接药效物质，发现新药苗子或先导结构提供科学依据，为同类研究提供有益参考。

通过对两种结构类型（螺甾烷和呋甾烷）的知母皂苷抗抑郁活性和体内代谢的研究，以知母皂苷代谢产物结构为模版，人工合成制备多个代谢产物及代谢产物衍生物。药理筛选结果表明人工合成化合物YY-21和YY-23的抗抑郁药效显著，起效时间明显快于一线抗抑郁药物氟西汀。YY-21的抗抑郁作用可能通过NMDA受体的非竞争性抑制产生。以上研究为从知母皂苷研发新型抗抑郁创新药物提供了实验依据，奠定了一定的化学和药理基础。