Investigation of Neoclerodanes as Novel Opioid Ligands

新克莱丹作为新型阿片类配体的研究

基本信息

批准号：
9030515
负责人：
THOMAS EDWARD PRISINZANO
金额：
$ 48.75万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030515
关键词：
Affinity Agonist Anxiety Behavioral Biological Assay Biological Markers Central Nervous System Diseases Chemicals Cocaine Comorbidity Development Dose Drug Addiction Dynorphins Effectiveness Evaluation FDA approved Funding Generations Genus Mentha Goals HIV-1 Hallucinations Hallucinogens Health Care Costs Hepatitis B Hepatitis C In Vitro Investigation Laboratories Lead Ligands Literature Mediating Mental Depression Methamphetamine Modeling Modification Motor Activity Mus Neuropeptides Neurosecretory Systems Opioid Opioid Receptor Parents Pharmaceutical Preparations Pharmacology Plants Post-Traumatic Stress Disorders Preparation Progress Reports Property Psychostimulant dependence Public Health Relapse Reporting Research Research Personnel Rewards Salvia Sedation procedure Signal Transduction Terpenes Testing Toxic effect Work addiction analog base decalin design dysphoria experience improved in vivo innovation kappa opioid receptors nanomolar neoclerodane neuropsychiatric disorder neuropsychiatry nonhuman primate novel pharmacophore preference psychostimulant public health relevance receptor salvinorin A stress related disorder targeted treatment transmission process

项目摘要

DESCRIPTION (provided by applicant): Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric co-morbidity, and also enhances transmission of HIV-1, hepatitis B and C and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. Growing evidence shows that that κ opioid (KOP) receptors (and their endogenous high-efficacy agonist neuropeptides, the dynorphins) are involved in the modulation of major abuse-related effects of psychostimulants, and particularly relapse. The plant-derived hallucinogen, salvinorin A (a neoclerodane), from the mint Salvia divinorum, is a structurally unique KOP-agonist. Reference KOP-r agonists and salvinorin A can decrease certain psychostimulant-induced effects, but these desirable actions are accompanied by undesirable effects, including the aforementioned hallucinations, sedation and dysphoria/aversion. Selected novel semi-synthetic neoclerodanes from the previous period of this Project have potential as "lead" pharmacotherapeutic agents for psychostimulant addiction, as shown by their in vitro and in vivo profiles in translational models, including a reduced burden of undesirable behavioral effects. The central hypothesis of this proposal is that iterative structural modification of these neoclerodane "leads" will generate novel opioid receptor ligands with the potential to treat psychostimulant addiction, relapse, and co-morbid neuropsychiatric disorders. The Specific Aims of this proposal are (1) optimize the activity of novel neoclerodanes, including innovative synthetic trans-decalin analogs, at KOP receptors; (2) determine and optimize the in vivo activity of novel neoclerodanes as KOPr ligands in mice, and for their ability to decrease cocaine-induced effects; and (3) determine and optimize the activity of novel neoclerodanes prioritized from Aims 1 and 2, in translational non- human primate models. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design, synthesis, evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically useful KOP-r targeted medications for the treatment of drug addiction.

描述（由适用提供）：对可卡因和甲基苯丙胺的成瘾，高度添加性的心理刺激剂，与大量神经精神病的合并症有关，还可以增强HIV-1，HIV-1，乙型肝炎，乙型肝炎和C的传播，从而导致巨大的公共健康成本。目前没有FDA批准的精神刺激成瘾治疗方法。越来越多的证据表明，κ阿片类药物（KOP）受体（及其内源性高效能激动剂神经肽，dynorphins）参与了对精神刺激剂的主要滥用相关作用的调节，尤其是继电器。植物来源的致幻蛋白A（来自薄荷salvia divinorum的新氯烷）是一种在结构上独特的Kop-agenist。参考kop-r激动剂和萨尔维诺蛋白A可以减少某些心理刺激剂诱导的效果，但是这些理想的作用是通过不受欢迎的效果来实现的，包括Priore幻觉，镇静和烦躁不安/厌恶。该项目上一个时期的精选新型半合成新阶层具有潜力作为心理刺激成瘾的“铅”药物治疗剂，如其体外和体内概况所示，在翻译模型中，包括减少不良行为效应的燃烧。该提议的核心假设是，这些新氯烷“ Leads”的迭代结构修饰将产生新型的阿片类受体配体，并具有治疗精神刺激成瘾，继电器和共同发生神经精神疾病的潜力。该提案的具体目的是（1）优化KOP受体在KOP受体上的新型新氏霉菌的活性，包括创新的合成反式甲素类似物；（2）确定并优化新型新氏烷的体内活性作为小鼠中的Kopr配体，并为它们降低可卡因诱导的作用的能力；（3）在转化非人类主要模型中，确定并优先确定和优化了从目标1和2优先考虑的新型新氏霉菌的活性。拟议的研究具有创新性，因为新杂志是一类独特的阿片类药物配体。这些分子的设计，合成，评估将对旨在与阿片类受体相互作用的新药物问题的发展产生广泛的影响。预计该信息将促进临床上有用的KOP-R靶向药物治疗药物成瘾的药物。