Pharmacology and Metabolism of Salvia divinorum

描述（由申请人提供）：多种植物源性精神活性产品，如鼠尾草、佩奥特仙人掌和曼陀罗，可供公众轻易获得，且不受 FDA 或 DEA 监管。由于这些产品是天然的，许多公众可能会认为它们是安全的。然而，这些具有精神活性的天然产物的滥用潜力和健康风险尚未得到充分研究，特别是新出现的 S. divinorum。因此，迫切需要研究其活性成分、其代谢物和作用机制。 S. divinorum 经常通过肺部熏制和吸收。可以想象，熏制的 Salvinorin A（从 S. divinorum 中分离出的主要生物活性化合物）的初始代谢发生在肺部，而口服的 Salvinorin A 可能发生在肝脏中。所提出的新代谢物的分离和表征是为了提供急需的信息，了解代谢物是否具有活性，以及​​这些代谢物如何在体内储存和处理。该应用的总体目标是重点关注 S. divinorum 生物活性化合物和代谢物的分离、提取和表征，并通过体外受体结合和功能测定以及体内测试了解作用机制。我们的具体目标是 1) 继续对 S. divinorum 中其他潜在的 k 活性配体进行全面分离和表征； 2）研究S. divinorum的活性烟气降解产物； 3) 研究已鉴定产品的吸收、分布和代谢情况； 4) 表征salvinorin A及其类似物和代谢物的体外和体内药理活性。更好地了解从 S. divinorum 中分离出的 k 种特定天然产物及其代谢物可能为发现新配体和开发治疗药物成瘾和其他神经系统疾病的潜在药物疗法提供机会。

DESCRIPTION (provided by applicant): A variety of plant-derived psychoactive products such as Salvia divinorum, peyote cactus, and Datura stramonium are readily available to the general public and unregulated by the FDA or DEA. Since these products are natural, much of the public may assume that they are safe. However, the abuse potential and health risks of these psychoactive natural products have not been adequately studied, especially the newly emerged S. divinorum. Thus, there is an urgent need to investigate the active components, their metabolites, and mechanisms of action. S. divinorum is often smoked and absorbed through the lungs. It is conceivable that the initial metabolism of smoked salvinorin A, the major bioactive compound isolated from S. divinorum, takes place in the lung, whereas orally consumed salvinorin A may take place in the liver. The proposed isolation and characterization of new metabolites is to provide much needed information on whether metabolites are active or not, and how these metabolites are stored in and disposed of by the body. The overall objective of this application is to focus on the isolation, extraction, and characterization of bioactive compounds and metabolites of S. divinorum and to understand mechanisms of action through in vitro receptor binding and functional assays and in vivo tests. Our specific aims are 1) to continue our comprehensive isolation and characterization of other potential k-active ligands in S. divinorum; 2) to investigate the active smoke degradation products of S. divinorum; 3) to investigate the absorption, distribution, and metabolism aspects of the identified products; 4) to characterize in vitro and in vivo pharmacological activities of salvinorin A and its analogs and metabolites. A better understanding of k specific natural products isolated from S. divinorum and its metabolites may provide an opportunity for the discovery of novel ligands and the development of potential pharmacotherapies for treating drug addiction and other neurological disorders.