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，高度成瘾性精神兴奋剂，与大量神经精神病发病率相关，并增加HIV-1、B肝炎和丙型肝炎以及耐药性结核病的传播，从而造成巨大的公共卫生成本。目前，没有FDA批准的治疗精神兴奋剂滥用的方法。越来越多的证据表明，？阿片样物质（KOP）受体参与调节精神兴奋剂的某些滥用相关作用。值得注意的是，重复或慢性精神兴奋剂给药导致KOP受体/强啡肽系统的延长上调。KOP受体/强啡肽系统是大脑对增强的多巴胺能活性的反调节反应的主要部分，多巴胺能活性是精神兴奋剂诱导的强化和滥用潜力的主要初始事件。Kappa阿片受体也与鼠尾草的作用有关，鼠尾草是一种致幻薄荷植物，目前尚未上市，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的流行程度增加，DEA最近将其列入药物名单。可以预见，其滥用将迅速增加。该提议的中心假设是鼠尾草素A的结构修饰将导致鉴定具有治疗药物依赖及其复发的潜力的新型κ阿片样物质受体配体。本研究的长期目标是开发新克罗烷衍生的KOP配体，其在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）中具有药理学潜力。该提案的具体目的是（1）优化新氯烷对KOP受体的活性;（2）鉴定具有KOP活性的新型天然新氯烷;和（3）测定化合物的体内生物活性。拟议的研究是创新的，因为新氯烷是一类独特的阿片受体配体。这些分子的设计、合成、分离和评估将对旨在与KOP受体相互作用的新型药理探针的开发产生广泛影响。这一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。 公共卫生相关性：兴奋剂依赖是一种慢性复发性疾病，由药物对大脑的长期影响引起。目前，没有FDA批准的治疗药物可用于治疗兴奋剂滥用或预防其复发。该项目旨在开发新克罗丹衍生物？阿片样物质（KOP）受体配体在精神兴奋剂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PTSD）中具有药理学潜力。这些分子的设计、合成、分离和评估将对旨在与KOP受体相互作用的新型药理探针的开发产生广泛影响。这一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.