Investigation of Neoclerodanes as Novel Opioid Ligands

兴奋剂滥用（如可卡因和甲基苯丙胺）是美国的一个主要公共卫生问题。 CMS兴奋剂的滥用加剧了HIV-1、B肝炎和丙型肝炎以及药物的影响和进展 耐药结核病大量证据表明，κ阿片受体可能参与了 调节CNS兴奋剂的某些滥用相关作用。因此，κ阿片受体提供了一种 治疗兴奋剂滥用及其伴随的病理学的药理学靶点，以及各种类型的 痛苦κ阿片受体也与致幻药鼠尾草（Salvia divinorum）的作用有关。 薄荷植物，目前是不定期和随时可供公众在互联网上。由于近期 随着鼠尾草在欧洲和美国青少年中的普及，DEA已经 最近把它列入了药物监控名单可以预见，其滥用将迅速增加。在 此外，很少有研究已经进行了对丹参或其药理作用模式， 活性成分鼠尾草素A。这一建议的中心假设是， 鼠尾草素A将导致鉴定具有治疗药物的潜力的新型κ阿片受体配体。 依赖和复发。这项研究的长期目标是更全面地了解kappa的作用 阿片受体在治疗药物依赖以及致幻活性中的功能。具体 该建议的目的是（1）基于以下结构鉴定κ阿片受体的新配体： 天然产物鼠尾草素A和（2）鉴定结构构象对鼠尾草素A的亲和力的作用， 活动本提案中采用的创新方法利用了药物化学，体外 药理学和体内药理学来实现我们的目标。该提案是一个新的模板， κ阿片受体配体在药物依赖和镇痛中的研究。

Stimulant abuse (e.g cocaine and methamphetamine) is a major public health problem in the United States. The abuse of CMS stimulants potentiates the impact and progression of HIV-1, hepatitis B and C, and drug resistant tuberculosis. A large body of evidence indicates that kappa opioid receptors may be involved in the modulation of some abuse related effects of CNS stimulants. Thus, kappa opioid receptors offer a pharmacological target to treat stimulant abuse and its attendant pathology, as well as, various types of pain. Kappa opioid receptors have also been implicated in the actions of Salvia divinorum, a hallucinogenic mint plant that is currently unscheduled and readily available to the public over the internet. Due to the recent increase in the popularity of Salvia divinorum among both European and American teens, the DEA has recently placed it on the list of drugs to watch. It is predictable that its misuse will increase rapidly. In addition, few studies have been conducted on the pharmacological mode of action of Salvia divinorum or its active component, salvinorin A. The central hypothesis of this proposal is that structural modification of salvinorin A will lead to identification of novel kappa opioid receptor ligands with the potential to treat drug dependence and its relapse. The long-term goal of this research is to more fully understand the role of kappa opioid receptor function in treating drug dependence, as well as in hallucinogenic-like activity. The specific aims of this proposal are (1) identify novel ligands for kappa opioid receptors based on the structure of the natural product salvinorin A and (2) identify the role of structural conformation on salvinorin A's affinity and activity. The innovative approach employed in this proposal utilizes medicinal chemistry, in vitro pharmacology and in vivo pharmacology to achieve our goals. This proposal represents a new template for the study of kappa opioid receptors ligands in drug dependence and analgesia.