Pharmacology and Metabolism of Salvia divinorum

描述(申请人提供)：各种植物来源的精神活性产品，如丹参、仙人掌和曼陀罗，对公众来说很容易获得，不受FDA或DEA的监管。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还没有得到充分的研究，特别是新出现的Divinorum。因此，迫切需要研究其活性成分、代谢产物和作用机制。Divinorum经常被烟熏并通过肺部吸收。可想而知，烟熏丹参甲素的初始代谢发生在肺，而口服丹参甲素可能发生在肝脏。新的代谢物的分离和鉴定是为了提供关于代谢物是否活跃以及这些代谢物是如何在体内储存和处置的急需的信息。这一应用的总体目标是集中于分离、提取和鉴定Divinorum的生物活性化合物和代谢物，并通过体外受体结合、功能分析和体内试验了解其作用机制。我们的具体目标是：1)继续全面分离和鉴定Divinorum中其他潜在的k-活性配体；2)研究Divinorum活性烟雾降解产物；3)研究已鉴定产物的吸收、分布和代谢方面；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Divinorum及其代谢物中分离出的k个特定的天然产物，可能为发现新的配体和开发治疗药物成瘾和其他神经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.