Investigation of Neoclerodanes as Novel Opioid Ligands

描述（由申请人提供）：可卡因和甲基苯丙胺成瘾是高度成瘾性的精神兴奋剂，与大量神经精神疾病有关，也会增加艾滋病毒1型、乙型和丙型肝炎以及耐药结核病的传播，从而造成巨大的公共卫生成本。目前，FDA还没有批准精神兴奋剂滥用的治疗方法。越来越多的证据表明？阿片样物质（KOP）受体参与调节一些与精神兴奋剂滥用有关的影响。值得注意的是，反复或慢性精神兴奋剂的使用会导致KOP受体/啡肽系统的长期上调。KOP受体/ dynorphin系统是大脑对多巴胺能活性增强的反调节反应的主要部分，这是精神兴奋剂诱导的强化和滥用潜在的主要初始事件。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。本研究的核心假设是，salvinorin A的结构修饰将导致鉴定出具有治疗药物依赖及其复发潜力的新型kappa阿片受体配体。本研究的长期目标是开发具有药物治疗潜力的新克罗丹衍生的KOP配体，用于治疗精神兴奋剂成瘾和复发，以及神经精神疾病（包括焦虑、抑郁和应激相关疾病，如PTSD）。本提案的具体目的是：(1)优化新氯烷类药物在KOP受体上的活性；(2)鉴定具有KOP活性的新型天然新氯罗德类药物；(3)测定化合物在体内的生物活性。提出的研究是创新的，因为新氯罗丹是一类独特的阿片受体配体。这些分子的设计、合成、分离和评价将对设计用于与KOP受体相互作用的新药理学探针的开发产生广泛的影响。这一信息有望促进临床有用的KOP靶向药物的鉴定，用于治疗药物滥用和主要神经精神疾病。

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.