Investigation of Neoclerodanes as Novel Opioid Ligands

描述（由申请人提供）：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兴奋剂的滥用增强了HIV-1、乙型和丙型肝炎以及耐药结核病的影响和进展。大量证据表明，kappa阿片受体可能参与中枢神经系统兴奋剂滥用相关效应的调节。因此，kappa阿片受体为治疗兴奋剂滥用及其伴随的病理以及各种类型的疼痛提供了一个药理学靶点。Kappa阿片受体也与鼠尾草（Salvia divinorum）的作用有关，鼠尾草是一种致幻薄荷植物，目前未被列入计划，公众可以通过互联网随时获得。由于最近鼠尾草在欧洲和美国青少年中越来越受欢迎，美国缉毒局最近将其列入了值得关注的药物名单。可以预见，它的滥用将迅速增加。此外，关于鼠尾草及其活性成分salvinorin A的药理作用模式的研究很少。本研究的中心假设是salvinorin A的结构修饰将导致鉴定出具有治疗药物依赖和复发潜力的新型kappa阿片受体配体。本研究的长期目标是更充分地了解kappa阿片受体功能在治疗药物依赖以及致幻剂样活性中的作用。本提案的具体目的是：(1)基于天然产物salvinorin A的结构确定kappa阿片受体的新型配体；(2)确定结构构象对salvinorin A的亲和力和活性的作用。本提案采用的创新方法利用药物化学，体外药理学和体内药理学来实现我们的目标。这为kappa阿片受体配体在药物依赖和镇痛中的研究提供了一个新的模板。

DESCRIPTION (provided by applicant): 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.