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（由申请人提供）：对可卡因和甲基苯丙胺（高度成瘾的精神兴奋剂）的成瘾与大量的神经精神共病有关，并且还会增加 HIV-1、乙型和丙型肝炎的传播，从而导致巨大的公共卫生成本。越来越多的证据表明，κ 阿片类药物 (KOP) 受体（及其内源性高效激动剂神经肽）尚未获得 FDA 批准。强啡肽）参与调节精神兴奋剂的主要滥用相关作用，特别是复发。来自植物鼠尾草的迷幻剂 Salvinorin A（一种新氯丹）是一种结构独特的 KOP 激动剂。 r激动剂和salvinorin A可以减少某些精神兴奋剂引起的作用，但这些理想的作用伴随着不良作用，包括上述幻觉、镇静和烦躁/厌恶。本项目前期选定的新型半合成新克莱丹有潜力作为精神兴奋剂成瘾的“主要”药物治疗剂，如转化模型中的体外和体内概况所示。该提案的中心假设是，这些新克罗丹“先导物”的迭代结构修饰将产生新型阿片受体配体，具有治疗精神兴奋剂成瘾、复发和共病神经精神疾病的潜力。该提案的目的是 (1) 优化新型新环丹的活性，包括创新的合成反式十氢萘类似物，对 KOP 受体的活性；(2) 确定和优化体内活性；新型新克罗丹作为 KOPr 配体在小鼠中的活性，以及其降低可卡因诱导效应的能力；以及 (3) 在转化非人类灵长类动物模型中确定和优化优先考虑目标 1 和 2 的新型新克罗丹的活性。创新是因为新克莱丹是一类独特的阿片受体配体，这些分子的设计、合成和评估将对旨在与阿片类药物相互作用的新药理学探针的开发产生广泛的影响。该信息有望促进临床上有用的 KOP-r 靶向药物的识别，用于治疗药物成瘾。