Investigation of Neoclerodanes as Novel Opioid Ligands

兴奋剂滥用(如可卡因和甲基苯丙胺)在美国是一个主要的公共卫生问题。 CMS兴奋剂的滥用加剧了HIV-1、乙肝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，kappa阿片受体可能参与了 中枢神经系统兴奋剂滥用相关效应的调制。因此，kappa阿片受体提供了 治疗兴奋剂滥用的药理学目标及其伴随的病理，以及各种类型的 疼痛。Kappa阿片受体也与迷幻药丹参的作用有关。 目前没有计划的薄荷厂，公众可以通过互联网随时获得。由于最近 在欧美青少年中，丹参越来越受欢迎，DEA已经 最近，它被列入了需要观察的药物名单。可以预见的是，它的滥用将迅速增加。在……里面 此外，对丹参或其药理作用模式的研究较少。 活性成分丹参素A这一提议的中心假设是 Salvinorin A将导致发现具有治疗药物潜力的新型kappa阿片受体配体 依赖及其故态复萌。这项研究的长期目标是更充分地理解kappa的作用。 阿片受体在治疗药物依赖以及致幻活性方面发挥作用。具体的 这项建议的目的是(1)根据kappa阿片受体的结构识别新的配体 天然产物Salvinorin A和(2)鉴定结构构象对Salvinorin A亲和力的作用 活动。这项提案中采用的创新方法是利用体外药物化学。 药理学和体内药理学来实现我们的目标。该提案代表了一个新的模板 Kappa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.