Investigation of Neoclerodanes as Novel Opioid Ligands

描述(申请人提供)：对可卡因和甲基苯丙胺的上瘾是高度上瘾的精神刺激剂，与大量的神经精神疾病有关，并增加艾滋病毒-1、乙肝和丙型肝炎的传播，以及抗药性结核病，从而造成巨大的公共卫生成本。目前，还没有FDA批准的治疗精神刺激性药物滥用的方法。越来越多的证据表明了这一点？阿片(KOP)受体参与了精神刺激剂的某些滥用相关效应的调节。值得注意的是，反复或长期服用精神刺激剂会导致KOP受体/强啡肽系统的长期上调。Kop受体/强啡肽系统是大脑对增强的多巴胺能活性做出反调节反应的主要部分，这是心理刺激剂诱导的强化和滥用潜力的主要初始事件。Kappa阿片受体也与丹参的作用有关，丹参是一种迷幻薄荷植物，目前未列入计划，公众可以通过互联网随时获得。由于最近丹参在欧洲和美国青少年中越来越受欢迎，DEA最近将其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。这一建议的中心假设是，Salvinorin A的结构修饰将导致发现新的kappa阿片受体配体，具有治疗药物依赖及其复发的潜力。这项研究的长期目标是开发具有治疗精神刺激性成瘾和复发以及神经精神障碍(包括焦虑、抑郁和应激相关障碍，如创伤后应激障碍)的药物治疗潜力的新十字烷衍生KOP配体。这项建议的具体目标是：(1)优化KOP受体上的新甾烷类化合物的活性；(2)鉴定具有KOP活性的新天然新类甾烷类化合物；(3)确定化合物在体内的生物活性。这项拟议的研究具有创新性，因为新甾烷是一类独特的阿片受体配体。这些分子的设计、合成、分离和评估将对设计用于与KOP受体相互作用的新的药理探针的开发产生广泛的影响。这些信息预计将有助于确定临床上有用的KOP靶向药物，用于治疗药物滥用和主要的神经精神疾病。 与公共卫生相关：兴奋剂依赖是一种慢性复发性疾病，由药物对大脑的长期作用引起。目前，还没有FDA批准的治疗剂可用于治疗兴奋剂滥用或防止其复发。该项目寻求开发新景天烷衍生物？阿片(KOP)受体配体在精神刺激性成瘾和复发以及神经精神障碍(包括焦虑、抑郁和与压力相关的疾病，如创伤后应激障碍)中具有药物治疗潜力。这些分子的设计、合成、分离和评估将对设计用于与KOP受体相互作用的新的药理探针的开发产生广泛的影响。这些信息预计将有助于确定临床上有用的KOP靶向药物，用于治疗药物滥用和其他神经精神疾病。

DESCRIPTION (provided by applicant): Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric morbidity, as well as enhancing transmission of HIV-1, hepatitis B and C, and drug resistant tuberculosis, and thus causing massive public health costs. Presently, there are no FDA approved treatments for psychostimulant abuse. A growing body of evidence has shown that ? opioid (KOP) receptors are involved in the modulation of some of the abuse related effects of psychostimulants. Notably, repeated or chronic psychostimulant administration results in a prolonged upregulation of the KOP receptor/ dynorphin system. The KOP receptor/ dynorphin system is a major part of the brain's counter-regulatory esponse to enhanced dopaminergic acitivity, which is a major initial event underlying psychostimulant-induced reinforcement and abuse potential. 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. 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 develop neoclerodane-derived KOP ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD). The specific aims of this proposal are (1) optimize the activity of neoclerodanes at KOP receptors; (2) identify novel naturally occurring neoclerodanes with KOP activity; and (3) determine the biological activity of compounds in vivo. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design, synthesis, isolation, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP receptors. This information is expected to facilitate the identification of clinically useful KOP- targeted drugs for the treatment of drug abuse and major neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Stimulant dependence is a chronic relapsing disease that results from the prolonged effects of drugs on the brain. At present, there are no FDA-approved therapeutic agents available for the treatment of stimulant abuse or for the prevention of its relapse. This project seeks develop neoclerodane-derived ? opioid (KOP) receptor ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD). The design, synthesis, isolation, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP receptors. This information is expected to facilitate the identification of clinically useful KOP-targeted drugs for the treatment of drug abuse and other neuropsychiatric disorders.