Investigation of Neoclerodanes as Novel Opioid Ligands

新克莱丹作为新型阿片类配体的研究

• 批准号: 9266380
• 负责人: THOMAS EDWARD PRISINZANO
• 金额: $ 43.69万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 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/9266380
• 关键词: Affinity; Agonist; Anxiety; Behavioral; Biological Assay; Biological Markers; Central Nervous System Diseases; Chemicals; Clinical; 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

 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（高度成瘾性精神兴奋剂）的成瘾与大量的神经精神共病有关，并且还会增强 HIV-1、乙型和丙型肝炎的传播，从而造成巨大的公共卫生成本。目前尚无 FDA 批准的治疗精神兴奋剂成瘾的治疗方法。越来越多的证据表明，κ 阿片类药物 (KOP) 受体（及其内源性高效激动剂神经肽，强啡肽）参与调节精神兴奋剂的主要滥用相关效应，特别是复发。植物源致幻剂 salvinorin A（一种新氯丹）来自薄荷鼠尾草 (Salvia divinorum)，是一种结构独特的 KOP 激动剂。参考KOP-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，包括前面提到的幻觉、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， 包括减少不良行为影响的负担。该提案的中心假设是，这些新克莱丹“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。该提案的具体目标是（1）优化新型新环丹（包括创新的合成反式十氢化萘类似物）对 KOP 受体的活性； (2) 确定并优化新型新克莱丹作为 KOPr 配体在小鼠体内的活性，以及​​它们降低可卡因诱导作用的能力； (3) 在转化非人类灵长类动物模型中确定并优化优先考虑目标 1 和 2 的新型新氯丹的活性。拟议的研究具有创新性，因为新氯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受体相互作用的新型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，用于治疗毒瘾。